JP4841543B2 - Novel pyrrolo (2,3-b) pyridine derivatives, preparation and their pharmaceutical use in the form of kinase inhibitors - Google Patents

Description

  The present invention relates to a novel pyrrolo (2,3-b) pyridine derivative, a process for its production, its use as a pharmaceutical, a pharmaceutical composition containing it, and a regulatable state by inhibiting the activity of protein kinases. It relates to the pharmaceutical use of such derivatives in prevention and treatment.

  The present invention relates to a novel pyrrolo (2,3-b) pyridine derivative having an inhibitory effect on protein kinases.

  Thus, the products of the present invention can be used in particular in the prevention and treatment of conditions that can be modulated by inhibiting the activity of protein kinases.

  Inhibition and regulation of protein kinases, in particular, constitutes a powerful new mechanism of action in treating a large number of solid tumors.

  Thus, such conditions that can be treated by the products of the present application are most particularly solid tumors.

  Such protein kinases are in particular IGF1, Raf, EGF, PDGF, VEGF, Tie2, KDR, Flt1-3, FAK, Src, Abl, cKit, cdk1-9, Aurora1-2, cdc7, Akt, Pdk, S6K, It belongs to the group of Jnk, IR, FLK-1, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, PLK, Pyk2.

  More particularly, such protein kinases belong to the group IGF1, cdc7, Aurora1-2, Src, Jnk, FAK, KDR, IR, Tie2.

  The protein kinase IGF1 (insulin growth factor-1) is specifically designated.

  Thus, the present invention relates in particular to novel inhibitors of the IGF-1R receptor that can be used for oncological treatment.

  Cancer is still a disease that is apparently inadequate for existing therapies. Certain protein kinases play an important role in many cancers. Inhibition of such protein kinases can be important in cancer chemotherapy, particularly in suppressing tumor growth and survival. The present invention therefore relates to the identification of novel products that inhibit such protein kinases.

  Protein kinases are involved in signaling events that control cellular activation, proliferation and differentiation in response to extracellular mediators or environmental changes. These kinases belong to two groups: those that preferentially phosphorylate serine and / or threonine residues and those that preferentially phosphorylate tyrosine residues [SK Hanks and T. Hunter, FASEB, J. 1995, 9, pp. 576-596]. Serine / threonine kinases are, for example, protein kinase C isoforms [AC Newton, J. Biol. Chem., 1995, 270, pp. 28495-28498] and groups of cyclin-dependent kinases such as cdc2 [J. Pines, Trends in Biochemical Sciences, 1995, 18, pp. 195-197]. Tyrosine kinases include growth factor receptors such as epidermal growth factor (EGF) receptor [S. Iwashita and M. Kobayashi, Cellular Signaling, 1992, 4, pp. 123-132] and p56tck, p59fYn, ZAP-70. And cytoplasmic kinases such as csk kinase [C. Chan et al., Ann. Rev. Immunol., 1994, 12, pp. 555-592].

  Abnormally high levels of protein kinase activity due to abnormal cell function has been suggested in many diseases. This controls, for example, kinase activity associated with mutations, overexpression or inappropriate activation of kinase enzymes or overproduction or reduced production of cytokines or growth factors that are also involved in signaling upstream or downstream of kinases Can cause direct or indirect causes of dysfunction in the underlying mechanism. In any of these cases, there is hope that selective inhibition of kinase action will have a beneficial effect. Type 1 receptor for insulin-like growth factor (IGF-IR) is a transmembrane receptor with tyrosine kinase activity that binds to IGFI first but also binds to IGFII and insulin with relatively low affinity. To do. Binding of IGFI to its receptor results in oligomerization of the receptor, activation of tyrosine kinases, intermolecular autophosphorylation and phosphorylation of cellular substrates (major substrates: IRS1 and Shc). Receptors activated by the ligand induce mitotic activity in normal cells. However, IGF-IR plays an important role in “abnormal” growth.

  Several clinical reports highlight the important role of the IGF-I pathway in human cancer development. In many tumor types (breast, large intestine, lung, sarcoma, etc.), IGF-IR is often overexpressed, and the presence of IGF-IR is a more invasive phenotype. Often accompanied.

  High concentrations of circulating IGF1 are strongly correlated with prostate cancer, lung cancer and breast cancer risk.

  Furthermore, it has been widely shown that IGF-IR is required to establish and maintain a transformed phenotype in vitro as well as in vivo [Baserga R, Exp. Cell, Res., 1999, 253, 253, pp. 1-6]. IGF-IR kinase activity is essential for the transformation activity of several oncogenes: EGFR, PDGFR, SV40 viral large T antigen, activated Ras, Raf and v-Src. IGF-IR expression in normal fibroblasts induces a malignant phenotype, which in turn can result in tumor formation in vivo. The expression of IGF-IR plays an important role in substrate-independent growth. IGF-IR has also been shown to be a protective agent in chemotherapy-induced and radiation-induced apoptosis and cytokine-induced apoptosis. Furthermore, inhibition of endogenous IGF-IR by dominant inhibition, triple helix formation or antisense expression results in suppression of in vitro transformation activity and reduced tumor growth in animal models.

  One subject of the present invention is a product of formula (I).

式中、
Ｒは、水素を表すか、Ｒ２およびＲ３の要素から選択され、
Ｒ１は、−ＣＯ−ＮＲ７Ｒ８、−ＮＲ７Ｒ８、遊離もしくはエステル化されたカルボキシル、ヒドロキシル、アルコキシもしくはハロゲン原子で置換されていても良いアルケニルもしくはアルキルを表し、
Ｒ２およびＲ３は、同一でも異なっていても良く、−ＣＯ−ＮＲ７Ｒ８、−ＮＲ７Ｒ８、アルコキシ、アルコキシ−ＮＲ７Ｒ８、遊離もしくはエステル化されたカルボキシルまたはそれ自体が置換されていても良いフェニルで置換されていても良いアルキルもしくは−Ｏ−アルキルを表し、
Ｒ４、Ｒ５およびＲ６は同一でも異なっていても良く、水素原子、ハロゲン原子およびシアノ、アミノ、および置換されていても良いアルコキシもしくはアルキル基から選択され、Ｒ４は、下記のもの：カルボキシアルデヒド−ＣＨ＝Ｏ、ホルムアルドキシム−ＣＨ＝Ｎ−ＯＨおよびメチルヒドロキシルアミン−ＣＨ_２ＮＨＯＨから選択されても良く、
Ｒ７およびＲ８は、同一でも異なっていても良く、水素、アルキル、アルケニル、シクロアルキル、シクロアルケニル、ヘテロシクロアルキル、アリールおよびヘテロアリールから選択され、これらは単環式もしくは二環式であることができ、これらの基はいずれも置換されていても良いか、あるいはＲ７およびＲ８は、これらが結合している窒素原子とともに、Ｏ、Ｓ、ＮおよびＮＲ１４から選択される１以上のヘテロ原子を有する不飽和または部分飽和もしくは完全飽和の３〜１０員の複素環基を形成しており、この基は置換されていても良く、
上記のアルキル、アルケニル、シクロアルキル、シクロアルケニル、ヘテロシクロアルキル、アリールおよびヘテロアリール基(これらは単環式もしくは二環式であることができる。)のいずれも、ならびにまたＲ７およびＲ８によってこれらが結合している窒素原子とともに形成された複素環基は、ハロゲン原子およびシアノ、ヒドロキシル、アルキル、アルコキシ、アルキルチオ、ニトロ、オキソ、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、シクロアルキルアルキル、ヘテロシクロアルキルアルキル、アリールアルキル、ヘテロアリールアルキル、−Ｃ（＝Ｏ）−Ｒ９、−Ｃ（＝Ｏ）−ＯＲ１０、−Ｎ（Ｒ１１）−Ｃ（＝Ｏ）−Ｒ９、−Ｎ（Ｒ１１）−Ｃ（＝Ｏ）−ＯＲ１０、−ＮＲ１２Ｒ１３、−Ｃ（＝Ｏ）−ＮＲ１２Ｒ１３、−Ｎ（Ｒ１１）−Ｃ（＝Ｏ）−ＮＲ１２Ｒ１３、−Ｓ（Ｏ）ｎ−Ｒ９、−Ｎ（Ｒ１１）−Ｓ（Ｏ）ｎ−Ｒ９、−Ｓ（Ｏ）ｎ−ＮＲ１２Ｒ１３および−Ｎ（Ｒ１１）−Ｓ（Ｏ）ｎ−ＮＲ１２Ｒ１３基から選択される同一でも異なっていても良い１個以上の基で置換されていても良く、
ｎは、０〜２の整数を表し、
後者のアルキル、アルコキシ、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、シクロアルキルアルキル、ヘテロシクロアルキルアルキル、アリールアルキルおよびヘテロアリールアルキル基自体は、ハロゲン原子およびヒドロキシル、アルキル、アルコキシ、−ＮＲ１２Ｒ１３、遊離もしくはエステル化されたカルボキシル、ＣＦ_３、ニトロ、シアノ、フェニルおよびフェニルアルキル基から選択される同一でも異なっていても良い１個以上の基で置換されていても良く、前記フェニル基はそれ自体、ハロゲン原子およびヒドロキシル、アルキル、アルコキシ、遊離もしくはエステル化されたカルボキシル、ＣＦ_３、ニトロ、シアノおよびピリジル基から選択される同一でも異なっていても良い１個以上の基で置換されていても良く、
Ｒ９は、アルキル、アルケニル、シクロアルキル、ヘテロ−シクロアルキル、アリール、ヘテロアリール、シクロアルキルアルキル、ヘテロ−シクロアルキルアルキル、アリールアルキルおよびヘテロアリールアルキルを表し、これらの基はいずれも置換されていても良く、
Ｒ１０は、Ｒ９の要素および水素を表し、
Ｒ１１は、水素もしくは置換されていても良いアルキルを表し、
Ｒ１２およびＲ１３は、同一でも異なっていても良く、水素、アシル、アルキル、シクロアルキル、ヘテロシクロアルキル、ヘテロアリール、ＳＯ_２−ヘテロアリール、−ＳＯ_２−アルキル、−ＳＯ_２−フェニル、−ＣＯ−ＮＨ−フェニルおよびフェニル基を表し、これらの基はいずれも置換されていても良く、
あるいはＲ１２およびＲ１３は、これらが結合している窒素原子とともに、Ｏ、Ｓ、ＮおよびＮＲ１４から選択される１以上のヘテロ原子を有する不飽和もしくは部分飽和もしくは完全飽和の３〜１０員の複素環基を形成しており、この基は置換されていても良く、
Ｒ１４は、Ｒ９の要素および水素、アシルならびに遊離およびエステル化されたカルボキシルを表し、
上記の基Ｒ９、Ｒ１０、Ｒ１１、Ｒ１２、Ｒ１３およびＲ１４は、ならびにＲ１２およびＲ１３によってこれらが結合している窒素原子とともに形成されていても良い環状基は、ハロゲン原子およびアルキル、アルキル−ＮＨ_２、アルキル−ＮＨＣＯ_２アルキル、ＮＨ_２、ＮＨＣＯ_２アルキル、ヒドロキシル、アルコキシ、ヒドロキシアルコキシ、遊離もしくはエステル化されたカルボキシル、ＣＦ_３、ＳＣＦ_３、ＯＣＦ_３、ＯＣＨＦ_２、ＳＯ_２ＣＦ_３、ニトロ、シアノ、ヘテロシクロアルキル、ヘテロアリールおよびフェニル基から選択される同一でも異なっていても良い１個以上の基で置換されていても良く、後者の環状基自体は、ハロゲン原子およびアルキル、ヒドロキシル、アルコキシ、遊離もしくはエステル化されたカルボキシル、ＣＦ_３、ＳＣＦ_３、ＯＣＦ_３、ＯＣＨＦ_２，ＳＯ_２ＣＦ_３、ＮＨ_２、ＮＨＣＯ_２アルキル、ニトロおよびシアノ基から選択される同一でも異なっていても良い１個以上の基で置換されていても良く、
上記のアリール、ヘテロアリールおよびヘテロシクロアルキル基はいずれも、さらに、アルキレンジオキシ基で置換されていても良く、
上記のアルキル、アルケニル、アルコキシもしくは−Ｏ−アルキルおよびアルキルチオ基はいずれも、直鎖もしくは分岐であり、６個以下の炭素原子を有し、
上記のシクロアルキル基はいずれも、７個以下の炭素原子を有し、
上記のアリール、ヘテロアリールおよびヘテロシクロアルキル基はいずれも、１０個以下の炭素原子を有し、
前記式（Ｉ）の製造物は、ラセミ体、エナンチオマーもしくはジアステレオマー異性体型、および前記式（Ｉ）の製造物の無機酸および有機酸とのまたは無機塩基および有機塩基との付加塩であっても良い。

Where
R represents hydrogen or is selected from the elements of R2 and R3;
R1 represents -CO-NR7R8, -NR7R8, a free or esterified carboxyl, hydroxyl, alkoxy or alkenyl or alkyl optionally substituted with a halogen atom;
R2 and R3 may be the same or different and are substituted with —CO—NR7R8, —NR7R8, alkoxy, alkoxy-NR7R8, free or esterified carboxyl or phenyl which may itself be substituted. Represents good alkyl or -O-alkyl,
R4, R5 and R6 may be the same or different and are selected from hydrogen atoms, halogen atoms and cyano, amino, and optionally substituted alkoxy or alkyl groups, wherein R4 is: Carboxaldehyde-CH ═O, formaldoxime—CH═N—OH and methylhydroxylamine—CH ₂ NHOH,
R7 and R8 may be the same or different and are selected from hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl and heteroaryl, which may be monocyclic or bicyclic And any of these groups may be substituted, or R7 and R8 have one or more heteroatoms selected from O, S, N and NR14 together with the nitrogen atom to which they are attached. Forming an unsaturated or partially saturated or fully saturated 3- to 10-membered heterocyclic group, which group may be substituted,
Any of the above alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl and heteroaryl groups (which can be monocyclic or bicyclic), and also by R7 and R8 they are Heterocyclic groups formed with the attached nitrogen atoms are halogen atoms and cyano, hydroxyl, alkyl, alkoxy, alkylthio, nitro, oxo, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocyclo Alkylalkyl, arylalkyl, heteroarylalkyl, -C (= O) -R9, -C (= O) -OR10, -N (R11) -C (= O) -R9, -N (R11) -C ( = O) -OR10, -NR12R13, -C (= O) NR12R13, -N (R11) -C (= O) -NR12R13, -S (O) n-R9, -N (R11) -S (O) n-R9, -S (O) n-NR12R13 and -N (R11) -S (O) n-NR12R13 may be substituted with one or more groups, which may be the same or different, selected from the group,
n represents an integer of 0 to 2,
The latter alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl and heteroarylalkyl groups themselves are halogen atoms and hydroxyl, alkyl, alkoxy, —NR12R13, free Or may be substituted with one or more groups, which may be the same or different, selected from esterified carboxyl, CF ₃ , nitro, cyano, phenyl and phenylalkyl groups, said phenyl group itself being Substituted by halogen atoms and one or more groups which may be the same or different selected from hydroxyl, alkyl, alkoxy, free or esterified carboxyl, CF ₃ , nitro, cyano and pyridyl groups May have been
R9 represents alkyl, alkenyl, cycloalkyl, hetero-cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, hetero-cycloalkylalkyl, arylalkyl and heteroarylalkyl, any of which may be substituted well,
R10 represents an element of R9 and hydrogen;
R11 represents hydrogen or optionally substituted alkyl;
R12 and R13 may be the same or different, hydrogen, acyl, alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, SO ₂ - heteroaryl, -SO ₂ - alkyl, -SO ₂ - phenyl, -CO- NH-phenyl and phenyl groups, both of which may be substituted,
Alternatively, R12 and R13 are an unsaturated or partially saturated or fully saturated 3 to 10 membered heterocyclic ring having one or more heteroatoms selected from O, S, N and NR14 together with the nitrogen atom to which they are attached. Forming a group, which may be substituted,
R14 represents the element of R9 and hydrogen, acyl and free and esterified carboxyl;
The above groups R9, R10, R11, R12, R13 and R14, and the cyclic group which may be formed together with the nitrogen atom to which they are bonded by R12 and R13, are a halogen atom and alkyl, alkyl-NH ₂ , Alkyl-NHCO ₂ alkyl, NH ₂ , NHCO ₂ alkyl, hydroxyl, alkoxy, hydroxyalkoxy, free or esterified carboxyl, CF ₃ , SCF ₃ , OCF ₃ , OCHF ₂ , SO ₂ CF ₃ , nitro, cyano, hetero It may be substituted with one or more groups which may be the same or different selected from cycloalkyl, heteroaryl and phenyl groups, the latter cyclic group itself being a halogen atom and alkyl, hydroxyl, alkoxy, free or Esterified _{Carboxyl, CF 3, SCF 3, OCF} 3, OCHF 2, SO 2 CF 3, NH 2, NHCO 2 alkyl, substituted with nitro and groups may also be one or more be the same or different selected from a cyano group It ’s okay,
Any of the above aryl, heteroaryl and heterocycloalkyl groups may be further substituted with an alkylenedioxy group,
All of the above alkyl, alkenyl, alkoxy or —O-alkyl and alkylthio groups are straight-chain or branched and have 6 or fewer carbon atoms,
Any of the above cycloalkyl groups have 7 or fewer carbon atoms,
All of the above aryl, heteroaryl and heterocycloalkyl groups have up to 10 carbon atoms,
The product of formula (I) is a racemic, enantiomeric or diastereomeric isomer form, and addition salts of the product of formula (I) with inorganic and organic acids or with inorganic and organic bases. May be.

Thus, one subject of the present invention is
R represents hydrogen or is selected from the elements of R2 and R3;
R1 represents -CO-NR7R8, -NR7R8, free or esterified carboxyl, hydroxyl, alkoxy or alkenyl or alkyl optionally substituted with a halogen atom;
R2 and R3 may be the same or different, and may be substituted with —CO—NR7R8, —NR7R8, alkoxy, alkoxy-NR7R8, free or esterified carboxyl, or phenyl which may be substituted. Represents good alkyl or -O-alkyl,
R4, R5 and R6 may be the same or different and are selected from a hydrogen atom, a halogen atom and cyano, amino and an optionally substituted alkoxy or alkyl group; R4 is: Carboxaldehyde-CH = O, it is selected from formaldoxime -CH = N-OH and methyl hydroxylamine _-CH 2 NHOH well;
R7 and R8 may be the same or different and are selected from hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl and heteroaryl (which can be monocyclic or bicyclic). Any of these groups may be substituted, or R7 and R8 have one or more heteroatoms selected from O, S, N and NR14 together with the nitrogen atom to which they are attached. Forming an unsaturated or partially saturated or fully saturated 3- to 10-membered heterocyclic group, which group may be substituted,
Any of the above alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl and heteroaryl groups, which can be monocyclic or bicyclic, and also by R7 and R8 The heterocyclic group formed together with the nitrogen atom to which is bonded is a halogen atom and cyano, hydroxyl, alkyl, alkoxy, alkylthio, nitro, oxo, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, hetero Cycloalkylalkyl, arylalkyl, heteroarylalkyl, -C (= O) -R9, -C (= O) -OR10, -N (R11) -C (= O) -R9, -N (R11) -C (= O) -OR10, -NR12R13, -C (= O -NR12R13, -N (R11) -C (= O) -NR12R13, -S (O) n-R9, -N (R11) -S (O) n-R9, -S (O) nNR12R13 and -N ( R11) -S (O) n-NR12R13 may be the same or different and may be substituted with one or more groups selected from
n represents an integer of 0 to 2;
The latter alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl and heteroarylalkyl groups themselves are halogen atoms and hydroxyl, alkyl, alkoxy, —NR12R13, free Alternatively, it may be substituted with one or more groups which may be the same or different selected from esterified carboxyl, CF ₃ , nitro, cyano, phenyl and phenylalkyl groups, in which case the phenyl group is As such, it may be the same or different, selected from halogen atoms and hydroxyl, alkyl, alkoxy, free or esterified carboxyl, CF ₃ , nitro, cyano and pyridyl groups. May be substituted with the above groups,
R9 represents alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl and heteroarylalkyl, any of these groups may be substituted,
R10 represents an element of R9 and hydrogen;
R11 represents hydrogen or optionally substituted alkyl;
R12 and R13 are, may be the same or different, hydrogen, acyl, alkyl, cycloalkyl, piperidyl, piperazinyl, pyrrolidinyl, azetidinyl, pyrazolyl, pyridyl, imidazolyl, pyrimidyl, thiazolyl, thiazolidinyl, -SO ₂ - thienyl, -SO ₂ - pyridyl, -SO ₂ - alkyl, -SO ₂ - phenyl, represents -CO-NH- phenyl and phenyl group, any of these groups may be substituted,
Or R12 and R13, together with the nitrogen atom to which they are attached, an unsaturated or partially saturated or fully saturated 3-10 membered heterocyclic ring having one or more heteroatoms selected from O, S, N and NR14 Forming a group, which may be substituted,
R14 represents the element of R9 and hydrogen, acyl and free and esterified carboxyl;
The above-mentioned groups R9, R10, R11, R12, R13 and R14, and the cyclic group which may be formed together with the nitrogen atom to which they are bonded by R12 and R13, are a halogen atom and an alkyl, —CH ₂ —NH _{2, -CH} 2 -NHCO _{2 alkyl,} NH 2, NHCO ₂ alkyl, hydroxyl, alkoxy, hydroxyalkoxy, free or esterified _{carboxyl, CF 3, SCF 3, OCF} 3, OCHF 2, SO 2 CF 3, nitro , Cyano, piperidyl, morpholinyl, piperazinyl, thienyl, pyridyl, imidazolyl, thiazolyl, thiazolidinyl and phenyl group, which may be substituted with one or more groups, the latter cyclic group itself Is a halogen atom and And the same or different selected from alkyl, hydroxyl, alkoxy, free or esterified carboxyl, CF ₃ , SCF ₃ , OCF ₃ , OCHF ₂ , SO ₂ CF ₃ , NH ₂ , NHCO ₂ alkyl, nitro and cyano groups Optionally substituted with one or more groups,
Any of the above aryl, heteroaryl and heterocycloalkyl groups may be further substituted with an alkylenedioxy group,
Any of the above alkyl, alkenyl, alkoxy or —O-alkyl and alkylthio groups are straight-chain or branched and have 6 or fewer carbon atoms;
Any of the above cycloalkyl groups have 7 or fewer carbon atoms,
All of the above aryl, heteroaryl and heterocycloalkyl groups have 10 or fewer carbon atoms,
The product of formula (I) is a racemic, enantiomeric or diastereomeric isomer form, and addition salts of the product of formula (I) with inorganic and organic acids or with inorganic and organic bases. It may be a product of formula (I) as defined above and as defined in the present invention.

  One subject of the present invention is a product of formula (I)

式中、
Ｒは、水素を表すか、Ｒ２およびＲ３の場合の要素から選択され、
Ｒ１は、−ＣＯ−ＮＲ７Ｒ８、−ＮＲ７Ｒ８、遊離もしくはエステル化されたカルボキシル、ヒドロキシル、アルコキシもしくはハロゲン原子で置換されていても良いアルケニルもしくはアルキルを表し、
Ｒ２およびＲ３は、同一でも異なっていても良く、−ＣＯ−ＮＲ７Ｒ８、−ＮＲ７Ｒ８、ヒドロキシル、アルコキシ、アルコキシ−ＮＲ７Ｒ８、遊離もしくはエステル化されたカルボキシルまたは自体が置換されていても良いフェニルで置換されていても良いアルキルもしくは−Ｏ−アルキルを表し、
Ｒ４、Ｒ５およびＲ６は、同一でも異なっていても良く、水素原子、ハロゲン原子および置換されていても良いシアノ、アミノ、アルコキシもしくはアルキルの基から選択され、
Ｒ７およびＲ８は、同一でも異なっていても良く、水素、アルキル、アルケニル、シクロアルキル、シクロアルケニル、ヘテロシクロアルキル、アリールおよびヘテロアリール（これらは、単環式もしくは二環式であることができる。）から選択され、これらの基はいずれも置換されていても良く、あるいはＲ７およびＲ８は、これらが結合している窒素原子とともに、３〜１０環員からなり、Ｏ、Ｓ、ＮおよびＮＲ１４から選択される１以上のヘテロ原子を有する不飽和または部分飽和もしくは完全飽和の複素環基を形成しており、この基は置換されていても良く、上記のアルキル、アルケニル、シクロアルキル、シクロアルケニル、ヘテロシクロアルキル、アリールおよびヘテロアリール（単環式もしくは二環式であることができる。）のいずれも、ならびにまたＲ７およびＲ８によってこれらが結合している窒素原子とともに形成された複素環基は、ハロゲン原子およびシアノ、ヒドロキシル、アルキル、アルコキシ、アルキルチオ、ニトロ、オキソ、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、シクロアルキルアルキル、ヘテロシクロアルキルアルキル、アリールアルキル、ヘテロアリールアルキル、−Ｃ（＝Ｏ）−Ｒ９、−Ｃ（＝Ｏ）−ＯＲ１０、−Ｎ（Ｒ１１）−Ｃ（＝Ｏ）−Ｒ９、−Ｎ（Ｒ１１）−Ｃ（＝Ｏ）−ＯＲ１０、−ＮＲ１２Ｒ１３、−Ｃ（＝Ｏ）−ＮＲ１２Ｒ１３、−Ｎ（Ｒ１１）−Ｃ（＝Ｏ）ＮＲ１２Ｒ１３、−Ｓ（Ｏ）ｎ−Ｒ９、−Ｎ（Ｒ１１）−Ｓ（Ｏ）ｎ−Ｒ９、−Ｓ（Ｏ）ｎ−ＮＲ１２Ｒ１３および−Ｎ（Ｒ１１）−Ｓ（Ｏ）ｎ−ＮＲ１２Ｒ１３の基から選択される同一でも異なっていても良い１個以上の基で置換されていても良く、
ｎは、０〜２の整数を表し、
後者のアルキル、アルコキシ、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、シクロアルキルアルキル、ヘテロシクロアルキルアルキル、アリールアルキルおよびヘテロアリールアルキル基自体は、ハロゲン原子およびヒドロキシル、アルキル、アルコキシ、−ＮＲ１２Ｒ１３、遊離もしくはエステル化されたカルボキシル、ＣＦ_３、ニトロ、シアノ、ピロリジニルならびにフェニルおよびフェニルアルキルの基から選択される同一でも異なっていても良い１個以上の基で置換されていても良く、前記フェニル基はそれ自体、ハロゲン原子およびヒドロキシル、アルキル、アルコキシ、遊離もしくはエステル化されたカルボキシル、ＣＦ_３、ニトロ、シアノおよびピリジルの基から選択される同一でも異なっていても良い１個以上の基で置換されていても良く、
Ｒ９は、アルキル、アルケニル、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、シクロアルキルアルキル、ヘテロシクロアルキルアルキル、アリールアルキルおよびヘテロアリールアルキルを表し、これらの基はいずれも置換されていても良く、
Ｒ１０は、Ｒ９の要素および水素を表し、
Ｒ１１は、水素もしくは置換されていても良いアルキルを表し、
Ｒ１２およびＲ１３は、同一でも異なっていても良く、水素、アシル、アルキル、シクロアルキルおよびフェニルを表し、これらの基は置換されていても良く、あるいはＲ１２およびＲ１３は、これらが結合している窒素原子とともに、３〜１０環員からなり、Ｏ、Ｓ、ＮおよびＮＲ１４から選択される１以上のヘテロ原子を有する不飽和または部分飽和もしくは完全飽和の複素環基を形成しており、この基は置換されていても良く、
Ｒ１４は、Ｒ９における要素および水素、アシルおよび遊離およびエステル化されたカルボキシルを表し、
上記の基Ｒ９、Ｒ１０、Ｒ１１、Ｒ１２、Ｒ１３およびＲ１４は、ハロゲン原子およびアルキル、ヒドロキシル、アルコキシ、ヒドロキシアルコキシ、遊離もしくはエステル化されたカルボキシル、ＣＦ_３、ニトロ、シアノおよびフェニル (この基はそれ自体、ハロゲン原子およびアルキル、ヒドロキシル、アルコキシ、遊離もしくはエステル化されたカルボキシル、ＣＦ_３、ニトロおよびシアノの基から選択される同一でも異なっていても良い１個以上の基で置換されていても良い。) の基から選択される同一でも異なっていても良い１個以上の基で置換されていても良く、 上記のアリール、ヘテロアリールおよびヘテロシクロアルキル基はいずれも、さらに、アルキレンジオキシ基で置換されていても良く、
上記のアルキル、アルケニル、アルコキシもしくは−Ｏ−アルキルおよびアルキルチオ基はいずれも、直鎖もしくは分岐であり、６個以下の炭素原子を有し、
上記のシクロアルキル基はいずれも、７個以下の炭素原子を有し、
上記のアリール、ヘテロアリールおよびヘテロシクロアルキル基はいずれも、１０個以下の炭素原子を有し、
前記式（Ｉ）の製造物は、ラセミ体、エナンチオマーもしくはジアステレオマー異性体型、ならびに前記式（Ｉ）の製造物の無機酸および有機酸とのもしくは無機塩基および有機塩基との付加塩であっても良い。

Where
R represents hydrogen or is selected from the elements in the case of R2 and R3;
R1 represents -CO-NR7R8, -NR7R8, a free or esterified carboxyl, hydroxyl, alkoxy or alkenyl or alkyl optionally substituted with a halogen atom;
R2 and R3 may be the same or different and are substituted with —CO—NR7R8, —NR7R8, hydroxyl, alkoxy, alkoxy-NR7R8, free or esterified carboxyl or phenyl which may itself be substituted. Represents an alkyl or -O-alkyl,
R4, R5 and R6 may be the same or different and are selected from a hydrogen atom, a halogen atom and an optionally substituted cyano, amino, alkoxy or alkyl group;
R7 and R8 may be the same or different and may be hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl and heteroaryl, which may be monocyclic or bicyclic. And any of these groups may be substituted, or R7 and R8, together with the nitrogen atom to which they are attached, consist of 3 to 10 ring members from O, S, N and NR14. Forming an unsaturated or partially saturated or fully saturated heterocyclic group having one or more selected heteroatoms, which group may be substituted, and the above alkyl, alkenyl, cycloalkyl, cycloalkenyl, Heterocycloalkyl, aryl and heteroaryl (can be monocyclic or bicyclic) Both, and also the heterocyclic groups formed with the nitrogen atom to which they are attached by R7 and R8, are halogen atoms and cyano, hydroxyl, alkyl, alkoxy, alkylthio, nitro, oxo, cycloalkyl, heterocycloalkyl, Aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, -C (= O) -R9, -C (= O) -OR10, -N (R11) -C (= O) -R9, -N (R11) -C (= O) -OR10, -NR12R13, -C (= O) -NR12R13, -N (R11) -C (= O) NR12R13, -S (O) n-R9 , -N (R11) -S (O) n-R9, -S (O) n-NR12R13 and -N (R11)- (O) may be substituted by n-NR12R13 of may be the same or different selected from group 1 or more groups,
n represents an integer of 0 to 2,
The latter alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl and heteroarylalkyl groups themselves are halogen atoms and hydroxyl, alkyl, alkoxy, —NR12R13, free Alternatively, it may be substituted with esterified carboxyl, CF ₃ , nitro, cyano, pyrrolidinyl and one or more groups which may be the same or different and selected from phenyl and phenylalkyl groups, As such, it may be the same or different selected from halogen atoms and groups of hydroxyl, alkyl, alkoxy, free or esterified carboxyl, CF ₃ , nitro, cyano and pyridyl. May be substituted with one or more groups,
R9 represents alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl and heteroarylalkyl, any of which groups may be substituted,
R10 represents an element of R9 and hydrogen;
R11 represents hydrogen or optionally substituted alkyl;
R12 and R13 may be the same or different and represent hydrogen, acyl, alkyl, cycloalkyl and phenyl, these groups may be substituted, or R12 and R13 may be the nitrogen to which they are attached. Together with atoms form an unsaturated or partially saturated or fully saturated heterocyclic group consisting of 3 to 10 ring members and having one or more heteroatoms selected from O, S, N and NR14, May be replaced,
R14 represents the element in R9 and hydrogen, acyl and free and esterified carboxyl;
The above groups R9, R10, R11, R12, R13 and R14 are halogen atoms and alkyl, hydroxyl, alkoxy, hydroxyalkoxy, free or esterified carboxyl, CF ₃ , nitro, cyano and phenyl (this group itself , Halogen atoms and alkyl, hydroxyl, alkoxy, free or esterified carboxyl, CF ₃ , nitro and cyano, which may be substituted with one or more groups which may be the same or different. ) May be substituted with one or more groups selected from the same or different groups, and any of the above aryl, heteroaryl and heterocycloalkyl groups may be further substituted with an alkylenedioxy group May have been
All of the above alkyl, alkenyl, alkoxy or —O-alkyl and alkylthio groups are straight-chain or branched and have 6 or fewer carbon atoms,
Any of the above cycloalkyl groups have 7 or fewer carbon atoms,
All of the above aryl, heteroaryl and heterocycloalkyl groups have up to 10 carbon atoms,
The product of formula (I) is a racemic, enantiomeric or diastereomeric isomer form, and addition salts of the product of formula (I) with inorganic and organic acids or with inorganic and organic bases. May be.

Accordingly, one subject of the present invention is
R2 and R3 may be the same or different, have 4 or fewer carbon atoms, and may be substituted with —CO—NR7R8, —NR7R8, alkoxy, alkoxy-NR7R8, or a free or esterified carboxyl Represents good -O-alkyl,
Other substituents of the product of formula (I) have the elements defined above in the present invention, and the product of formula (I) is in racemic, enantiomeric or diastereomeric isomer form, and The product of formula (I) as defined above and as defined in the present invention may be an addition salt of the product of formula (I) with inorganic and organic acids or with inorganic bases and organic bases.

Thus, one subject of the present invention is that R2 and R3 may be the same or different and have 4 or fewer carbon atoms and are substituted with -CO-NR7R8, -NR7R8, alkoxy, alkoxy-NR7R8. Represents good -O-alkyl,
Other substituents of the product of formula (I) have the elements defined above and in the present invention,
The product of formula (I) is a racemic, enantiomeric or diastereomeric isomer form, and addition salts of the product of formula (I) with inorganic and organic acids or with inorganic and organic bases. It may be a product of formula (I) as defined above and as defined herein.

Accordingly, one subject of the present invention is -O-alkyl, wherein R2 and R3 may be the same or different and have at most 4 carbon atoms and may be substituted with -CO-NR7R8 or -NR7R8 Represents
Other substituents of the product of formula (I) have the elements defined above and in the present invention,
The product of formula (I) is a racemic, enantiomeric or diastereomeric isomer form, and addition salts of the product of formula (I) with inorganic and organic acids or with inorganic and organic bases. It may be a product of formula (I) as defined above and as defined herein.

Accordingly, one subject of the present invention represents R1 -CO-NR7R8, -NR7R8, free or esterified carboxyl, hydroxyl, alkoxy or alkyl optionally substituted with halogen atoms,
Other substituents of the product of formula (I) have the elements defined above and in the present invention,
The product of formula (I) is a racemic, enantiomeric or diastereomeric isomer form, and addition salts of the product of formula (I) with inorganic and organic acids or with inorganic and organic bases. It may be a product of formula (I) as defined above and as defined herein.

Accordingly, one subject of the present invention represents alkyl wherein R1 has 4 or fewer carbon atoms and may be substituted with -CO-NR7R8, -NR7R8, free or esterified carboxyl or hydroxyl,
Other substituents of the product of formula (I) have the elements defined above and in the present invention,
The product of formula (I) is a racemic, enantiomeric or diastereomeric isomer form, and addition salts of the product of formula (I) with inorganic and organic acids or with inorganic and organic bases. It may be a product of formula (I) as defined above and as defined herein.

Accordingly, one subject of the present invention represents R1 having 4 or fewer carbon atoms and optionally substituted with —CO—NR7R8, —NR7R8 or hydroxyl,
Other substituents of the product of formula (I) have the elements defined above and in the present invention,
The product of formula (I) is a racemic, enantiomeric or diastereomeric isomer form, and addition salts of the product of formula (I) with inorganic and organic acids or with inorganic and organic bases. It may be a product of formula (I) as defined above and as defined herein.

Accordingly, one subject of the present invention represents R1 having 4 or fewer carbon atoms and optionally substituted with -CO-NR7R8 or -NR7R8, wherein the other products of formula (I) The substituent has the elements defined above and in the present invention;
The product of formula (I) is a racemic, enantiomeric or diastereomeric isomer form, and addition salts of the product of formula (I) with inorganic and organic acids or with inorganic and organic bases. It may be a product of formula (I) as defined above and as defined herein.

Accordingly, one subject of the present invention represents alkyl wherein R1 has 4 or fewer carbon atoms and may be substituted with NR7R8,
Other substituents of the product of formula (I) have the elements defined above and in the present invention,
The product of formula (I) is a racemic, enantiomeric or diastereomeric isomer form, and addition salts of the product of formula (I) with inorganic and organic acids or with inorganic and organic bases. It may be a product of formula (I) as defined above and as defined herein.

Accordingly, one subject of the present invention is
R4, R5 and R6 each represents one hydrogen and the other may be the same or different and are selected from a hydrogen atom, a halogen atom and an optionally substituted cyano, amino or alkyl group. Yes,
Other substituents of the product of formula (I) have the elements defined above and in the present invention,
The product of formula (I) is a racemic, enantiomeric or diastereomeric isomer form, and addition salts of the product of formula (I) with inorganic and organic acids or with inorganic and organic bases. It may be a product of formula (I) as defined above and as defined herein.

Accordingly, one subject of the present invention is that R4, R5 and R6 may be the same or different, R5 and R6 may be selected from hydrogen and halogen atoms, and R4 may be the same or different from R5 and R6. , Halogen atoms and amino, carboxaldehyde-CH═O, formaldoxime-CH═N—OH, methylhydroxylamine-CH ₂ NHOH and alkyl groups (these are halogen atoms and cyano, hydroxyl, alkoxy, cycloalkyl, hetero And may be substituted with one or more groups, which may be the same or different, selected from cycloalkyl, phenyl, heteroaryl and —NR12R13 groups.
R, R1, R2, R3, R12 and R13 have the elements defined in any of the other claims;
The product of formula (I) is a racemic, enantiomeric or diastereomeric isomer form, and addition salts of the product of formula (I) with inorganic and organic acids or with inorganic and organic bases. It may be a product of formula (I) as defined above and as defined herein.

Accordingly, one subject of the present invention is
R4, R5 and R6 represent hydrogen, or two of these represent hydrogen, the third represents a halogen atom or a cyano group,
Other substituents of the product of formula (I) have the elements defined above and in the present invention,
The product of formula (I) is a racemic, enantiomeric or diastereomeric isomer form, and addition salts of the product of formula (I) with inorganic and organic acids or with inorganic and organic bases. It may be a product of formula (I) as defined above and as defined herein.

Accordingly, one subject of the invention is that R4, R5 and R6 represent hydrogen, the other substituents of the product of formula (I) above have the elements defined above and in the invention,
The product of formula (I) is a racemic, enantiomeric or diastereomeric isomer form, and addition salts of the product of formula (I) with inorganic and organic acids or with inorganic and organic bases. It may be a product of formula (I) as defined above and as defined herein.

Accordingly, one subject of the present invention is R4, R5 and R6 wherein two of these represent hydrogen, the third represents a halogen atom or a cyano group,
Other substituents of the product of formula (I) have the elements defined above and in the present invention,
The product of formula (I) is a racemic, enantiomeric or diastereomeric isomer form, and addition salts of the product of formula (I) with inorganic and organic acids or with inorganic and organic bases. It may be a product of formula (I) as defined above and as defined herein.

Accordingly, one subject of the present invention is R4, R5 and R6 wherein two of these represent hydrogen, the third represents a halogen atom,
Other substituents of the product of formula (I) have the elements defined above and in the present invention,
The product of formula (I) is a racemic, enantiomeric or diastereomeric isomer form, and addition salts of the product of formula (I) with inorganic and organic acids or with inorganic and organic bases. It may be a product of formula (I) as defined above and as defined herein.

Accordingly, one subject of the present invention is that R4, R5 and R6, two of these represent hydrogen, the third represents a chlorine or fluorine atom,
Other substituents of the product of formula (I) have the elements defined above and in the present invention,
The product of formula (I) is a racemic, enantiomeric or diastereomeric isomer form, and addition salts of the product of formula (I) with inorganic and organic acids or with inorganic and organic bases. It may be a product of formula (I) as defined above and as defined herein.

Thus, one subject of the present invention is R4, R5 and R6, wherein two of these represent hydrogen, the third represents a cyano group,
Other substituents of the product of formula (I) have the elements defined above and in the present invention,
The product of formula (I) is a racemic, enantiomeric or diastereomeric isomer form, and addition salts of the product of formula (I) with inorganic and organic acids or with inorganic and organic bases. It may be a product of formula (I) as defined above and as defined herein.

Accordingly, one subject of the present invention is that R6 represents hydrogen,
Other substituents of the product of formula (I) have the elements defined above and in the present invention,
The product of formula (I) is a racemic, enantiomeric or diastereomeric isomer form, and addition salts of the product of formula (I) with inorganic and organic acids or with inorganic and organic bases. It may be a product of formula (I) as defined above and as defined herein.

Accordingly, one subject of the present invention is that R5 and R6 represent hydrogen, R4 represents a halogen atom or a cyano group,
Other substituents of the product of formula (I) have the elements defined above and in the present invention,
The product of formula (I) is a racemic, enantiomeric or diastereomeric isomer form, and addition salts of the product of formula (I) with inorganic and organic acids or with inorganic and organic bases. It may be a product of formula (I) as defined above and as defined herein.

Accordingly, one subject of the present invention is that R4 and R6 represent hydrogen, R5 represents a fluorine atom,
Other substituents of the product of formula (I) have the elements defined above and in the present invention,
The product of formula (I) is a racemic, enantiomeric or diastereomeric isomer form, and addition salts of the product of formula (I) with inorganic and organic acids or with inorganic and organic bases. It may be a product of formula (I) as defined above and as defined herein.

  In the product of formula (I) and in the following description, the terms indicated have the following meanings:

  The term “Hal”, “halo” or “halogen” denotes a fluorine, chlorine, bromine or iodine atom.

  -The term "alkyl group" or "alk group" has the following 12 carbon atoms: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl , Tert-pentyl, neopentyl, hexyl, isohexyl, sec-hexyl, tert-hexyl, as well as heptyl, octyl, nonyl, decyl, undecyl and dodecyl groups and linear or branched positional isomers thereof Or a branched group is shown.

  Further mentioned are alkyl groups having up to 6 carbon atoms, in particular methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, linear or branched pentyl and linear Or there is a branched hexyl group.

  The term “alkylene group” has up to 12 carbon atoms, preferably up to 4 carbon atoms, for example ethenyl or vinyl, propenyl or allyl, 1-propenyl, n-butenyl, i-butenyl, 3 -Represents a linear or branched group selected from methylbut-2-enyl, n-pentenyl, hexenyl, heptenyl, octenyl, cyclohexylbutenyl and decenyl and their linear or branched positional isomers.

  Among the alkenyl elements, mention may be made in particular of allyl or butenyl.

  The term “alkoxy group” or “O-alkyl group” has up to 12 carbon atoms, preferably up to 6 carbon atoms, eg methoxy, ethoxy, propoxy, isopropoxy, linear, secondary or A linear or branched group selected from tertiary butoxy, pentoxy, hexoxy and heptoxy groups and their linear or branched positional isomers is shown.

The term “alkoxycarbonyl group” or “alkyl-O—CO— group” denotes a straight-chain or branched group having up to 12 carbon atoms, wherein the alkyl group has the meaning given above. Mention may be made, for example, of methoxycarbonyl and ethoxycarbonyl groups.
-The term "alkylenedioxy group" or "-O-alkylene-O-group" denotes a linear or branched group having 12 or less carbon atoms, wherein the alkylene group has the above meaning. Mention may be made, for example, of methylenedioxy and ethylenedioxy groups.

  -The term "alkylsulfinyl" or "alkyl-SO-" is a straight or branched chain having up to 12 carbon atoms, the alkyl group having the above meaning, preferably having 4 carbon atoms. Indicates a group.

The term “alkylsulfonyl” or “alkyl-SO ₂ —” has 12 carbon atoms or less, the alkyl group has the meaning given above, preferably linear or branched having 4 carbon atoms The group of is shown.

The term “alkylsulfonylcarbamoyl” or “alkyl-SO ₂ —NH—C (═O) —” has not more than 12 carbon atoms and the alkyl group has the above meaning, preferably 4 Represents a straight-chain or branched group having the following carbon atoms.

  The term “alkylthio” or “alkyl-S—” denotes a straight-chain or branched group having up to 12 carbon atoms, in particular representing the methylthio, ethylthio, isopropylthio and heptylthio groups.

  The term “cycloalkyl group” denotes a 3 to 10 membered monocyclic or bicyclic carbocyclic group, in particular a cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl group.

  -The term "-O-cycloalkyl group" refers to a group wherein the cycloalkyl group has the above meaning.

  The term “cycloalkenyl group” denotes a monocyclic or bicyclic non-aromatic carbocyclic group having at least one double bond and having 3 to 10 ring members, in particular cyclobutenyl, A cyclopentenyl or cyclohexenyl group;

  The term “cycloalkylalkyl group” denotes a group wherein cycloalkyl and alkyl are selected from those indicated above; This group thus represents, for example, the cyclopropylmethyl, cycloheptylmethyl, cyclohexylmethyl and cycloheptylmethyl groups.

  The term “acyl group” or “r—CO— group” has up to 12 carbon atoms, the group r being a hydrogen atom or alkyl, cycloalkyl, cycloalkenyl, cycloalkyl, heterocycloalkyl, aryl or Represents a heteroaryl group, and these groups represent straight or branched groups having the above-described and optionally substituted elements. The acyl group thus represents in particular CO-alkyl, CO-aryl or CO-heteroaryl. Mention may be made, for example, of the formyl, acetyl, propionyl, butyryl or benzoyl group, or the valeryl, hexanoyl, acryloyl, crotonoyl, carbamoyl, pyrrolidinylcarboxyl or furylcarboxyl group.

  The term “acyloxy group” is intended to mean an acyl-O— group wherein acyl has the meaning given above, and mention may be made of, for example, an acetoxy or propionyloxy group.

  The term “acylamino group” is intended to mean an acyl-NH group wherein acyl has the meaning given above.

  The term “aryl group” denotes an unsaturated monocyclic or unsaturated group consisting of a fused carbocycle. Examples of such aryl groups include phenyl or naphthyl groups.

  Of particular mention are phenyl groups.

  -The term "arylalkyl" is intended to mean a group derived from a combination of the aforementioned alkyl groups that may be substituted and also the aforementioned aryl groups that may be substituted. Mention may be made, for example, of benzyl, phenylethyl, 2-phenylethyl, triphenylmethyl or naphthalenemethyl groups.

  The term “heterocyclic group” is a 6-membered saturated carbocyclic group (heterocycloalkyl) interrupted by one or more heteroatoms, which may be the same or different, selected from oxygen, nitrogen and sulfur atoms ) Or an unsaturated carbocyclic group (heteroaryl).

  Heterocycloalkyl groups that may be mentioned in particular include dioxolane, dioxane, dithiolane, thiooxolane, thiooxane, oxiranyl, oxolanyl, dioxolanyl, piperazinyl, piperidyl, pyrrolidyl, imidazolidinyl, pyrazolidinyl, morpholinyl or tetrahydrofuryl, tetrahydrothienyl, chromanyl, dihydrobenzofuranyl , Indolinyl, piperidyl, perhydropyranyl, pyrindolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl or thio-azolidinyl, piperidyl, tetrahydrofuran-2-yl, imidazolinyl, dihydropyrrolyl, tetrahydropyrrolyl, diazepine, perhydro-1,4 -Diazepine, tetrahydropyrrolo [3,4-c] pyrrol-2-one, tetrahydro Include lolo [3,4-c] pyrrole-1,3-dione and 1,4-dioxa-8-azaspiro [4.5] decane group, none of these groups may be substituted.

  Among the heterocycloalkyl groups, mention may be made of piperazinyl, piperidyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, morpholinyl, thioazolidinyl, piperidyl group; tetrahydrofuran-2-yl, imidazolinyl, dihydropyrrolyl, tetrahydropyrrolyl, diazepine, Perhydro-1,4-diazepine, tetrahydropyrrolo [3,4-c] pyrrol-2-one, tetrahydropyrrolo [3,4-c] pyrrole-1,3-dione and 1,4-dioxa-8-azaspiro [ 4.5] There is a decane group, any of which may be substituted.

  The term “heterocycloalkylalkyl” is intended to mean a group in which the heterocycloalkyl and alkyl residues have the above-mentioned meanings.

  Among the 5-membered heteroaryl groups, mention may be made of furyl groups such as 2-furyl, thienyl groups such as 2-thienyl and 3-thienyl, and pyrrolyl, diazolyl, thiazolyl, thiadiazolyl, thiatriazolyl, isothiazolyl, oxazolyl, There are oxadiazolyl, 3- or 4-isoxazolyl, imidazolyl, pyrazolyl and isoxazolyl groups.

  Among the 6-membered heteroaryl groups, mention may be made in particular of pyridyl groups such as 2-pyridyl, 3-pyridyl and 4-pyridyl, and pyrimidyl, pyrimidinyl, pyridazinyl, pyrazinyl and tetrazolyl groups.

  As fused heteroaryl groups having at least one heteroatom selected from sulfur, nitrogen and oxygen, mention may be made of, for example, benzothienyl such as 3-benzothienyl, benzofuryl, benzopyranyl, benzofuranyl, benzopyrrolyl, benzimidazolyl Benzoxazolyl, thionaphthyl, indolyl, purinyl, quinolyl, isoquinolyl and naphthyridinyl.

  Among the fused heteroaryl groups, mention may be made in particular of benzothienyl, benzofuranyl, indolyl, quinolyl, benzimidazolyl, benzothiazolyl, furyl, imidazolyl, indolizinyl, isoxazolyl, isoquinolyl, isothiazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl , Pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, 1,3,4-thiadiazolyl, thiazolyl, and thienyl and triazolyl groups, which groups may be substituted as shown for heteroaryl groups.

The term “cyclic amine” denotes a 3 to 8 membered cycloalkyl group in which one carbon atom is replaced by a nitrogen atom, the cycloalkyl group having the meanings given above, O, S, SO ₂ , N or NR9 (R9 is as defined above) may have one or more other heteroatoms. Examples which may be mentioned as examples of such cyclic amines are, for example, pyrrolidinyl, piperidyl, morpholinyl, piperazinyl, indolinyl, pyrindolinyl and tetrahydroquinolyl groups, which groups may be substituted.

  The term “patient” refers not only to humans but also to other mammals.

  The term “prodrug” refers to a product that can be converted in vivo to a product of formula (I) via metabolic mechanisms (such as hydrolysis). For example, an ester of a product of formula (I) having a hydroxyl group can be converted to its parent molecule by in vivo hydrolysis. Alternatively, an ester of a product of formula (I) having a carboxyl group can be converted to its parent molecule by in vivo hydrolysis. Examples of esters of products of formula (I) having hydroxyl groups that may be mentioned include acetate esters, citrate esters, lactate esters, tartaric acid esters, malonic acid esters, oxalic acid esters, salicylic acid esters, propionic acid esters. , Succinic acid ester, fumaric acid ester, maleic acid ester, methylenebis-β-hydroxynaphthoic acid ester, gentisic acid ester, isethionic acid ester, di-p-tolyl tartaric acid ester, methanesulfonic acid ester, ethanesulfonic acid ester, benzenesulfone Acid esters, p-toluenesulfonic acid esters, cyclohexylsulfamic acid esters and quinic acid esters.

  Particularly useful esters of the product of formula (I) having a hydroxyl group include those described in Vanguard et al. (Bundgaard et al., J. Med. Chem., 1989, 32, page 2503-2507), etc. It can produce from the acid residue. In particular, these esters include substituted (aminomethyl) benzoic acid esters, dialkylaminomethylbenzoic acid esters (the two alkyl groups of which may be linked together, or may be oxygen atoms or substituted. May be interrupted by a good nitrogen atom, ie an alkylated nitrogen atom.), Or (morpholinomethyl) benzoic acid esters, such as 3- or 4- (morpholinomethyl) benzoic acid esters, and (4-alkylpiperazine-1 -Yl) benzoic acid esters, such as 3- or 4- (4-alkylpiperazin-1-yl) benzoic acid esters.

  The carboxyl group of the product of formula (I) may be chlorinated or esterified with various groups known to those skilled in the art. Among them, for example, the following compounds can be mentioned. It is not limited to the example.

Among the chloride compounds, for example 1 equivalent of an inorganic base such as sodium, potassium, lithium, calcium, magnesium or ammonium, or for example methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N, N-dimethylethanolamine, tris Organic bases such as (hydroxymethyl) aminomethane, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, lysine, arginine, histidine or N-methylglucamine;
-Among the esterified compounds there are alkyl groups which form alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl, these alkyl groups being chloromethyl, hydroxypropyl, methoxymethyl Substituted with a group selected from, for example, a halogen atom and a hydroxyl, alkoxy, acyl, acyloxy, alkylthio, amino or aryl group, such as in a propionyloxymethyl, methylthiomethyl, dimethylaminoethyl, benzyl or phenethyl group good.

  The term “esterified carboxyl” means a group such as an alkyloxycarbonyl group, for example methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butyl or tert-butyloxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyl or cyclohexyloxycarbonyl To do.

  Also mentioned are groups formed with easily cleavable ester residues such as methoxymethyl or ethoxymethyl groups; acyloxyalkyls such as pivaloyloxymethyl, pivaloyloxyethyl, acetoxymethyl or acetoxyethyl Groups: alkyloxycarbonyloxyalkyl groups such as methoxycarbonyloxymethyl or ethyl groups and isopropyloxycarbonyloxymethyl or ethyl groups;

  A list of such ester groups is found, for example, in European Patent EP0034536.

  The term “amidate carboxyl” means a group of the —CONR7R8 type as defined above or below.

  The term "alkylamino group" or "dialkylamino group" means that an alkyl group is preferably 1 to 4 carbons such as a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl group. It means a group having an atom. This gives, for example, methylamino, ethylamino, propylamino or butylamino groups (which can be linear or branched) and dimethylamino, diethylamino and methylethylamino groups. The amino group can have one or two heterocycles which may have another heteroatom. Mention may be made, for example, of pyrrolyl, imidazolyl, indolyl, piperidyl, morpholinyl and piperazinyl groups, in particular piperidyl, morpholinyl or piperazinyl groups.

  The term “carboxyl chloride” is intended to mean a salt formed, for example, with one equivalent of sodium, potassium, lithium, calcium, magnesium or ammonium. Further mentioned are salts formed with organic bases such as methylamine, propylamine, trimethylamine, diethylamine or triethylamine. Sodium salt is preferred.

  It is clear that if the product of formula (I) has an amino group which can be salified with an acid, its acid salt also forms part of the present invention. Mention may be made, for example, of hydrochloric acid or methanesulfonic acid and the resulting salts.

  Addition salts of the product of formula (I) with inorganic or organic acids include, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, propionic acid, acetic acid, trifluoroacetic acid, formic acid, Benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, oxalic acid, glyoxylic acid, aspartic acid, ascorbic acid, alkyl monosulfonic acids (eg methanesulfonic acid, ethanesulfonic acid or propanesulfonic acid), alkyl There may be salts formed with disulfonic acids (eg methane disulfonic acid or α, β-ethanedisulfonic acid), aryl monosulfonic acids (eg benzene sulfonic acid) and aryl disulfonic acids.

  It can be recalled that stereoisomerism can be defined in its broad sense as the isomerism of a compound having the same structural formula, but with various groups arranged in spatially different ways, in particular the substituents Such as in mono-substituted cyclohexanes that can be in axial or equatorial positions as well as in various possible rotational conformations of ethane derivatives. However, there is another type of stereoisomerism due to different spatial arrangements of substituents fixed either on the double bond or on the ring, often referred to as geometric isomerism or cis-trans isomerism. The term “stereoisomer” is used in this patent application in its broadest sense and therefore relates to all the compounds indicated above.

Accordingly, one subject of the present invention is that the substituents R, R1, R2, R3, R4, R5 and R6 of the product of formula (I) have the elements defined above and in the present invention, and the group —NR12R13 is , R12 and R13 are may be the same or different, a hydrogen atom and an acyl, alkyl, cycloalkyl, piperidyl, piperazinyl, pyrrolidinyl, azetidinyl, pyrazolyl, pyridyl, imidazolyl, pyrimidyl, thiazolyl, thiazolidinyl, -SO ₂ - thienyl - SO ₂ -pyridyl, —SO ₂ -alkyl, —SO ₂ -phenyl, —CO—NH-phenyl and a phenyl group are all represented by a halogen atom and the following group: alkyl; CH ₂ -NH _{2; CH 2} -NHCO _{2 alkyl;} NH 2; NHCO ₂ alkyl; Dorokishiru; alkoxy; hydroxyalkoxy; free or esterified _{carboxyl; CF 3; SCF 3; OCF} 3; OCHF 2; SO 2 CF 3; nitro; cyano; thienyl; piperidyl; themselves one or two alkyl groups Morpholino optionally substituted with; and phenyl (which itself is a halogen atom and alkyl, hydroxyl, alkoxy, free or esterified carboxyl, CF ₃ , SCF ₃ , OCH ₃ , OCHF ₂ , SO ₂ CF ₃ , NH ₂ , may be substituted with one or more groups which may be the same or different selected from NHCO ₂ alkyl, nitro and cyano groups. May be substituted with a group,
Alternatively, R12 and R13 are unsaturated or partially saturated or fully saturated 3 to 10 membered complex having one or more heteroatoms selected from O, S, N and NR11 together with the nitrogen atom to which they are bonded. This group forms a cyclic group, which is a halogen atom as well as the following groups: alkyl; —CH ₂ —NH ₂ ; CH ₂ —NHCO ₂ alkyl; NH ₂ ; NHCO ₂ alkyl; hydroxyl; alkoxy; Or esterified carboxyl; CF ₃ ; SCF ₃ ; OCF ₃ ; OCHF ₂ ; SO ₂ CF ₃ ; SO ₂ CF ₃ ; nitro; cyano; and piperidyl; morpholinyl; piperazinyl; thienyl; pyridyl, imidazolyl, thiazolyl, thiazolidinyl and phenyl groups themselves Are halogen atoms and atoms Substituted with one or more groups, which may be the same or different, selected from alkyl, hydroxyl, alkoxy, free or esterified carboxyl, CF ₃ , SCF ₃ , NH ₂ , NHCO ₂ alkyl, nitro and cyano groups And may be substituted with one or more groups, which may be the same or different, selected from
The product of formula (I) is a racemic, enantiomeric or diastereomeric isomer form, and addition salts of the product of formula (I) with inorganic and organic acids or with inorganic and organic bases. It may be a product of formula (I) as defined above and as defined herein.

In particular, R12 and R13 may be the same or different and are hydrogen; acyl (eg, alkyl-CO-, phenyl-CO-, pyrazolyl-CO-, pyridyl-CO-, imidazolyl-CO-, pyrimidyl-CO- or Thiazolyl-CO-); alkyl optionally substituted with thienyl, alkoxy or phenyl (which may itself be substituted with OCH ₃ , SCF ₃ , NHCO ₂ ALK or NH ₂ ); cycloalkyl; good piperidyl optionally substituted; piperazinyl, pyrrolidinyl, azetidinyl; optionally substituted with alkyl pyrazolyl; pyridyl, imidazolyl, pyrimidyl, thiazolyl, thiazolidinyl; -SO ₂ - thienyl; -SO ₂ - pyridyl; -SO ₂ - alkyl; -SO ₂ - phenyl Which may be substituted with OCF ₃ -CO-NH- phenyl; good _OCF 3 substituted and phenyl (which _itself, OCH 3, SCF _3, may be substituted by piperidyl or morpholino, the latter The group itself may be substituted with one or two alkyl groups.).

Accordingly, one subject of the invention is that R, R1, R2, R3, R4, R5 and R6 have the meaning given above and in the present invention, R7 and R8 may be the same or different, hydrogen, alkyl, Selected from cycloalkyl, phenyl, heterocycloalkyl and heteroaryl (which can be monocyclic or bicyclic), any of these groups can be substituted, or R7 and R8 can be Form an unsaturated or partially saturated or fully saturated heterocyclic group consisting of 3 to 10 ring members and having one or more heteroatoms selected from O, S, N and NR14 together with the nitrogen atom to which And this group may be substituted,
All of the above groups: alkyl, cycloalkyl, phenyl, heterocycloalkyl and heteroaryl (which can be monocyclic or bicyclic), and the nitrogen atom to which they are attached by R7 and R8 The heterocyclic group formed is a halogen atom as well as hydroxyl, oxo, nitro, alkyl, alkoxy, alkylthio, cycloalkyl, phenyl, heterocycloalkyl, heteroaryl, -C (= O) -R9, -C (= O) -OR10, -N (R11) -C (= O) -R9, -N (R11) -C (= O) -OR10, -NR12R13, -C (= O) -NR12R13 and -N (R11) -C It may be substituted with one or more groups which may be the same or different and selected from the group (═O) —NR12R13.
The latter alkyl, alkoxy, cycloalkyl, phenyl, heterocycloalkyl and heteroaryl groups themselves are derived from halogen atoms and hydroxyl, alkyl, alkoxy, -NR12R13, free or esterified carboxyl, pyrrolidinyl and phenyl and phenylalkyl groups. It may be substituted with one or more selected groups which may be the same or different, the phenyl group itself being a halogen atom and hydroxyl, alkyl, alkoxy, free or esterified carboxyl, CF ₃ Optionally substituted with one or more groups which may be the same or different selected from the group of nitro, cyano and pyridyl,
R9 represents alkyl, cycloalkyl, phenyl, heterocycloalkyl and heteroaryl, any of these groups may be substituted,
R10 represents the element and hydrogen in R9;
R11 represents hydrogen or optionally substituted alkyl;
R12 and R13 may be the same or different and each represents hydrogen, acyl, alkyl, cycloalkyl and phenyl, and these groups may be substituted;
Alternatively, R12 and R13 together with the nitrogen atom to which they are attached consist of 3 to 10 ring members and have one or more heteroatoms selected from O, S, N and NR11. Forming a saturated heterocyclic group, which may be substituted,
R14 represents hydrogen, acyl, free and esterified carboxyl, alkyl, cycloalkyl and phenyl (optionally substituted);
The above groups R9, R10, R11, R12, R13 and R14 are halogen atoms and alkyl, hydroxyl, alkoxy, hydroxyalkoxy, free or esterified carboxyl, CF ₃ , nitro, cyano and phenyl (in themselves halogen And may be substituted with one or more groups, which may be the same or different, selected from atoms and alkyl, hydroxyl, alkoxy, free or esterified carboxyl, CF ₃ , nitro and cyano groups. May be substituted with one or more groups which may be the same or different selected from the group, and all the phenyl and heteroaryl groups described above may be further substituted with a dioxole group, Alkyl, alkenyl, alkoxy or -O Alkyl and alkylthio groups is a straight or branched, having up to 4 carbon atoms,
All of the above cycloalkyl groups have no more than 7 carbon atoms,
All of the above heteroaryl and heterocycloalkyl groups have up to 10 carbon atoms;
The product of formula (I) is a racemic, enantiomeric or diastereomeric isomer form, and addition salts of the product of formula (I) with inorganic and organic acids or with inorganic and organic bases. It may be a product of formula (I) as defined above and as defined herein.

For example, R14 is a hydrogen atom; a cycloalkyl group; for example, hydroxyl, alkoxy, hydroxyalkoxy or phenyl (which may itself be substituted with one or more groups selected from a halogen atom and CF ₃ ), alkoxy. And an alkyl group which may be substituted with a dioxol group; for example, a heterocyclic group such as piperidyl or pyridyl; a phenyl group (which itself may be substituted with alkoxy, CF ₃ or halogen); free or esterified An acyl group such as —CO—CH ₃ or —CO-furyl.

  Examples of the heterocyclic group that the above group can represent are shown below. Among these heterocyclic groups described below, those having at least one nitrogen atom are those in which R7 and R8 can be formed together with the nitrogen atom to which they are bonded, and R12 and R13 are bonded to each other. It constitutes an example of a group that can be formed with a nitrogen atom. Accordingly, the following can be mentioned, but the invention is not limited to these.

  Pyrrolidinyl, piperidyl, pyrimidinyl, thienyl, thiazolyl, pyran, furyl, tetrahydrofuryl, tetrahydrofur-2-yl, imidazolinyl, imidazolyl, piperazinyl, indolyl, pyrrole, benzopyran, quinolyl, pyridyl, purinyl, morpholinyl, thiomorpholinyl, azetidinyl, Azepanyl, diazepine, spiro- [4.5] decane, pyrrolyl, 2H-pyrrolyl, piperidyl, indolinyl, pyrindolinyl, tetrahydroquinolyl, thiazolidinyl, naphthyridyl, quinazolinyl, dihydropyrrolyl, 1,4-dioxa-8-aza-spiro [4.5] Decane and tetrahydropyrrolo [3,4-c] pyrrolyl, any of which may be substituted.

  More particularly, when R12 and R13 together with the nitrogen atom to which they are attached form a cyclic group, the cyclic group may be selected from pyrrolidinyl, morpholinyl, piperazinyl, piperidyl and azetidinyl groups, Any group may be substituted as indicated above.

In particular, when R12 and R13 together with the nitrogen atom to which they are attached form a cyclic group, this cyclic group (which may itself be substituted with a piperidyl group or a hydroxyl group); azetidinyl (May itself be substituted with NH—CO ₂ alk, CH ₂ —NH ₂ —CO ₂ alk, CH ₂ —NH ₂ and NH ₂ ); and piperazinyl (as such, alkyl, phenylalkyl or phenyl Optionally substituted by one or more groups; optionally substituted by one or more groups selected from the phenyl group itself, OCF ₃ , OCHF ₂ , SCF ₃ and SO ₂ CF ₃ ). be able to.

One subject of the invention is in particular that R, R1, R2, R3, R4, R5 and R6 have the meanings given above and in the invention,
R7 and R8 may be the same or different and may be hydrogen, cycloalkyl, optionally substituted alkyl, optionally substituted phenyl, heterocycloalkyl and optionally substituted monocyclic or bicyclic. Selected from heteroaryl,
Or R7 and R8 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic group having one or more heteroatoms;
All the above alkyl, phenyl and heterocyclic groups, and the heterocyclic groups which R7 and R8 may form together with the nitrogen atom to which they are attached, are halogen atoms and hydroxyl; oxo; nitro; cycloalkyl; alkoxy; OCF _3; hydroxyalkoxy; alkylthio; acyl; free or esterified carboxyl; phenyl optionally substituted; optionally substituted amino; halogen atoms and hydroxyl, alkoxy, pyrrolidinyl, phenyl, and amino (which Alkyl, optionally substituted with one or more groups selected from the group of: pyrrolidinyl, piperidyl, pyridyl and piperazinyl (which themselves are hydroxyl, alkyl, alkoxy, free Or selected from the group of esterified carboxyl, phenyl and phenylalkyl (which may itself be substituted) and may be substituted with one or more groups. May be substituted with one or more groups,
The amino group is alkyl, hydroxyalkyl, alkoxyalkyl, acyl, phenyl and phenylalkyl (which may themselves be substituted; the phenyl and phenylalkyl groups are halogen atoms and hydroxyl, alkyl, alkoxy, CF ₃ , free Or may be substituted with one or more groups selected from esterified carboxyl, pyridyl and dioxol groups.) Substituted with one or two groups which may be the same or different May have been
All the alkyl and alkoxy groups are straight-chain or branched and have 4 or less carbon atoms;
The product of formula (I) is a racemic, enantiomeric or diastereomeric isomer form, and addition salts of the product of formula (I) with inorganic and organic acids or with inorganic and organic bases. It may be a product of formula (I) as defined above and as defined herein.

Thus, the radicals R7 and R8, which may be the same or different, can represent in particular hydrogen and optionally substituted alkyl, cycloalkyl, phenyl groups and optionally substituted heterocyclic groups, R7 And among the elements in R8, mention may be made, for example, of pyrimidinyl; thienyl; pyridyl; quinolyl; thiazolyl optionally substituted by one or two halogen atoms; substituted by one or more OCO alks May be substituted with halogen atoms and with one or more groups selected from alkyl, alkoxy, amino, alkylamino, dialkylamino and carboxyl groups esterified with free or alkyl groups Good phenyl; phenyl (which itself is a halogen atom, alkyl, alkoxy Alkyl substituted with one or more groups selected from amino, alkylamino, dialkylamino and free carboxyl or carboxyl esterified with an alkyl group; piperazinyl (which itself is an alk , Alkyl-substituted with one or more groups selected from alk-OH and pyridyl); alkyl substituted with imidazolyl; NH ₂ , NH alk, N (alk) ₂ , N Alkyl substituted with one or more groups selected from (alk) (phenylalkyl), N (alk) (aminoalkyl), N (alk)-(alkylaminoalkyl) and N (alk) (dialkylaminoalkyl) Alkynyl substituted with morpholinyl optionally substituted by 1 or 2 alk Alkyl substituted with pyrrolidinyl; alkyl substituted with piperidyl (which may itself be substituted with one or two alks); alkyl substituted with thiomorpholinyl; alkyl substituted with azetidinyl; There are alkyl substituted with azepanyl which may be substituted with oxo.

  The groups that R7 and R8 can form with the nitrogen atom to which they are attached include dihydropyrrolyl, 1,4-dioxa-8-azaspiro [4.5] decane or tetrahydropyrrolo [3,4-c] pyrrolyl. Groups, and any of these groups may be substituted.

  The groups that R7 and R8 can form with the nitrogen atom to which they are attached are in particular halogen atoms and alkyl, hydroxyl, alkoxy and phenyl (which itself is one or more selected from halogen atoms and alkyl and alkoxy groups). And may be substituted with one or more groups selected from the same or different groups.

  The pyrrolidinyl and quinazolinyl groups may in particular be substituted with oxo or thiooxo. The piperazinyl group may in particular be substituted with one or more groups selected from alk, alk-OH and pyridyl.

  Said acyl group in particular represents a —CO-alkyl group, a —CO-furyl group or a —CO-pyrrolidinyl group having an alkyl having up to 4 carbon atoms.

One subject of the invention more particularly has R, R1, R2, R3, R4, R5 and R6 as defined above and in the present invention,
R7 and R8 may be the same or different and are hydrogen and alkyl, cycloalkyl, phenyl and pyrrolidinyl, piperidyl, pyrimidinyl, thienyl, thiazolyl, pyran, furyl, tetrahydrofuryl, tetrahydrofur-2-yl, imidazolinyl, piperazinyl, Selected from heterocyclic groups such as indolyl, pyrrole, benzopyran, quinolyl, pyridyl, purinyl and morpholinyl, which groups may be substituted,
Or R7 and R8 together with the nitrogen atom to which they are attached, pyrrolidinyl, imidazolyl, morpholinyl, piperazinyl, piperidyl, thiazolyl, diazepine, spiro [4.5] decane, pyrrolyl, dihydropyrrolyl, tetrahydropyrrolyl, tetrahydropyrrolo [3,4-c] pyrrolyl, piperidyl, indolinyl, pyrindolinyl, tetrahydroquinolyl, thiazolidinyl, naphthyridyl, azetidine or quinazolinyl groups are formed, and these groups are all substituted Well,
The above alkyl, any phenyl and the heterocyclic group, a halogen atom, and hydroxyl; oxo; nitro; cycloalkyl; alkoxy; OCF _3; hydroxyalkoxy; alkylthio; acyl; free or esterified carboxyl; substituted Optionally substituted phenyl; optionally substituted amino; substituted with one or more groups selected from halogen atoms and groups of hydroxyl, alkoxyl, pyrrolidinyl, phenyl and amino (which may themselves be substituted) And pyrrolidinyl, piperidyl, pyridyl and piperazinyl (which themselves are hydroxyl, alkyl, alkoxy, free or esterified carboxyl, phenyl and phenylalkyl (which themselves are May be substituted.) Groups are being optionally substituted with one or more groups selected from the.) May be substituted with one or more groups selected from groups,
The amino group is alkyl, hydroxyalkyl, alkoxyalkyl, acyl, phenyl and phenylalkyl (which may themselves be substituted, and the phenyl and phenylalkyl groups are halogen atoms and hydroxyl, alkyl, alkoxy, CF ₃ One or two groups which may be the same or different and may be substituted with one or more groups selected from free or esterified carboxyl, pyridyl and dioxol groups) May be replaced with
The alkyl and alkoxy groups are both straight or branched and have 4 or fewer carbon atoms;
The product of formula (I) is a racemic, enantiomeric or diastereomeric isomer form, and addition salts of the product of formula (I) with inorganic and organic acids or with inorganic and organic bases. It may be a product of formula (I) as defined above and as defined herein.

One subject of the invention is in particular that R, R1, R2, R3, R4, R5 and R6 have the meanings given above and in the invention,
R7 and R8 may be the same or different and are hydrogen, cycloalkyl and alkyl, phenyl and (pyrrolidinyl, piperidyl, furyl, tetrahydrofuryl, tetrahydrofur-2-yl, imidazolinyl, piperazinyl, indolyl, pyrrolyl, benzopyranyl, Selected from heterocyclic groups (such as benzopyran-8-carboxylic, pyridyl, purinyl and morpholinyl), any of which may be substituted,
Or R7 and R8 together with the nitrogen atom to which they are attached, pyrrolidinyl, imidazolyl, morpholinyl, piperazinyl, piperidyl, thiazolyl, diazepine, spiro [4.5] decane, pyrrolyl, dihydropyrrolyl, tetrahydropyrrolyl and tetrahydropyrrolo Forming a heterocyclic group selected from [3,4-c] pyrrolyl group, any of these groups may be substituted,
All of the above alkyls, phenyl, and the heterocyclic groups that R7 and R8 may represent, or that R7 and R8 may form with the nitrogen atom to which they are attached, are oxo; cycloalkyl; CO-alkyl; Hydroxyl; alkoxy; hydroxyalkoxy; alkylthio; free or esterified carboxyl; optionally substituted phenyl; hydroxyl, alkoxyl, pyrrolidinyl, optionally substituted phenyl and (alkyl and optionally substituted) Alkyl optionally substituted with a group selected from amino; alkyl, hydroxyalkyl, alkoxyalkyl, CO-alkyl and phenyl (optionally substituted with one or two groups selected from good phenyl) This is itself replaced Amino, optionally substituted by one or two groups, which may be the same or different selected from: pyrrolidinyl, piperidyl, pyridyl and piperazinyl (which are free or esterified) Substituted with one or more groups selected from the group of: a group selected from carboxyl, alkyl, alkoxy, hydroxyl, phenylalkyl and optionally substituted phenyl. You may,
All the phenyl groups are substituted by halogen atoms and one or more groups which may be the same or different selected from hydroxyl, alkyl, alkoxy, CF ₃ , free or esterified carboxyl, pyridyl and dioxol groups May have been
The product of formula (I) is a racemic, enantiomeric or diastereomeric isomer form, and addition salts of the product of formula (I) with inorganic and organic acids or with inorganic and organic bases. It may be a product of formula (I) as defined above and as defined herein.

Thus, R7 and R8, in particular, together with the nitrogen atom to which they are attached, the following groups: pyrrolidinyl; imidazolyl; dihydropyrrolyl; 1,4-dioxa-8-azaspiro [4.5] decane; morpholinyl; Piperidyl; thiazolyl; diazepine; perhydro-1,4-diazepine; 4-methylperhydro-1,4diazepin-1-yl; tetrahydropyrrolo [3,4-c] pyrrol-2-one; tetrahydropyrrolo [3; 4-c] forms a group selected from pyrrole-1,3-dione,
These groups may be substituted with one or more groups as indicated above or described in the experimental section.

One subject of the invention more particularly has R, R1, R2, R3, R4, R5 and R6 as defined above and in the present invention,
R7 and R8 may be the same or different and have the following groups:
-Hydrogen;
-Benzopyran;
-Pyridyl which may itself be substituted by hydroxyl;
-Piperidyl which may itself be substituted with alkyl optionally substituted with phenyl;
-Purinyl;
-Hydroxy; alkoxy; alkylthio; pyridyl; imidazolinyl, indolyl; pyrrolyl; furyl; tetrahydrofuryl; Amino optionally substituted with one or two groups which may be different; pyrrolidinyl which may itself be substituted with an alkyl group; piperidyl which may itself be substituted with alkyl or phenylalkyl; Piperazinyl optionally substituted with alkyl; alkyl optionally substituted with one or more groups selected from dioxol or phenyl optionally substituted with free or esterified carboxyl;
-Phenyl optionally substituted with one or more groups selected from alkoxyl, piperidyl and piperazinyl, which may itself be substituted with an alkyl group;
Or R7 and R8 together with the nitrogen atom to which they are attached the following groups:
-Imidazolyl;
-Dihydropyrrolyl;
-1,4-dioxa-8-azaspiro [4.5] decane;
-Thiazolyl;
-Tetrahydropyrrolo [3,4-c] pyrrol-2-one;
-Tetrahydropyrrolo [3,4-c] pyrrole-1,3-dione;
-Pyridyl; an amino which may itself be substituted with an alkyl group and an acyl group; and a group selected from hydroxyl, alkoxy, pyrrolidinyl and amino (which may itself be substituted with a phenyl group). Pyrrolidinyl optionally substituted with a group selected from optionally substituted alkyl;
-1 morpholinyl optionally substituted with one or more alkyl groups;
-Oxo; cycloalkyl; acyl; carboxyl; pyridyl; alkyl having 4 or fewer carbon atoms (which itself is hydroxyl, alkoxy, hydroxyalkoxy having 4 or fewer carbon atoms and phenyl (which itself is a dioxol group) Of the phenyl optionally substituted with one or more groups selected from halogen atoms and hydroxyl, alkoxy and CF ₃ groups. Piperazinyl optionally substituted by one or more groups selected from the same or different groups;
-Piperidyl optionally substituted with one or more substituents selected from hydroxyl, alkyl, hydroxyalkyl and piperidyl;
-Forming a heterocyclic group selected from diazepine or perhydro-1,4-diazepine optionally substituted with an alkyl group (which may itself be substituted with pyrrolidinyl);
The product of formula (I) is a racemic, enantiomeric or diastereomeric isomer form, and addition salts of the product of formula (I) with inorganic and organic acids or with inorganic and organic bases. It may be a product of formula (I) as defined above and as defined herein.

One subject of the invention more particularly R, R1, R2, R3, R4, R5 and R6 has the meanings given above and in the invention,
R7 and R8 may be the same or different and may be hydrogen, alkyl (which may itself be substituted with a pyrrolidinyl or piperidyl group) and phenyl (which itself is substituted with an alkyl group). Or optionally substituted with one or more groups selected from piperazinyl groups), or R7 and R8 together with the nitrogen atom to which they are attached, morpholinyl; thiazolyl; alkyl group Diazepine or perhydro-1,4-diazepine optionally substituted with 1-tetrahydropyrrolo [3,4-c] pyrrol-2-one; oxo and alkyl (which itself is a hydroxyl, alkoxy or hydroxyalkoxy group) And may be the same or different selected from the group of Optionally substituted with more than five groups piperazinyl; hydroxyl, alkyl, forms a group selected from a good-piperidyl optionally substituted by hydroxyalkyl or piperidyl,
The alkyl and alkoxy groups have no more than 4 carbon atoms;
The product of formula (I) is a racemic, enantiomeric or diastereomeric isomer form, and addition salts of the product of formula (I) with inorganic and organic acids or with inorganic and organic bases. It may be a product of formula (I) as defined above and as defined herein.

In more detail, one subject of the present invention is:
R and R6 represent a hydrogen atom,
R1 represents an alkyl having 2 or less carbon atoms and optionally substituted with -CO-NR7R8 or -NR7R8;
R2 and R3 may be the same or different and represent -O-alkyl having 3 or less carbon atoms and optionally substituted with -CO-NR7R8 or -NR7R8;
One of R4 and R5 represents hydrogen and the other represents a halogen atom or a cyano group;
R7 and R8 have the meanings indicated above,
The product of formula (I) is a racemic, enantiomeric or diastereomeric isomer form, and addition salts of the product of formula (I) with inorganic and organic acids or with inorganic and organic bases. It may be a product of formula (I) as defined above.

One subject of the invention more particularly R, R1, R2, R3, R4, R5, R6, R7 and R8 have the meanings given above and in the invention,
Both R7 and R8 cannot represent hydrogen,
The product of formula (I) is a racemic, enantiomeric or diastereomeric isomer form, and addition salts of the product of formula (I) with inorganic and organic acids or with inorganic and organic bases. It may be a product of formula (I) as defined above and as defined herein.

In more detail, one subject of the present invention is:
R, R1, R2, R3, R4, R5 and R6 have the meanings given in any other claim, R7 and R8 represent one of R7 and R8 represents hydrogen or alkyl, The other is selected from elements in R7 and R8 as defined in any other claim, or R7 and R8, together with the nitrogen atom to which they are attached, are defined in any other claim. A heterocyclic group of
The product of formula (I) is a racemic, enantiomeric or diastereomeric isomer form, and addition salts of the product of formula (I) with inorganic and organic acids or with inorganic and organic bases. It may be a product of formula (I) as defined above and as defined herein.

Among the preferred manufactured articles of the present invention, mention may be made in more detail of the name:
2- {5,6-dimethoxy-1- [2- (4-methylpiperazin-1-yl) ethyl] -1H-indol-3-yl} -1H-pyrrolo [2,3-b] pyridine,
2- (4- {2- [5,6-Dimethoxy-3- (1H-pyrrolo [2,3-b] pyrid-2-yl) -indol-1-yl] ethyl} piperazin-1-yl) ethanol ,
2- (1- {2- [5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] pyrid-2-yl) -indol-1-yl] ethyl} piperid-4-yl) ethanol ,
1 ′-{2- [5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] pyrid-2-yl) -indol-1-yl] ethyl}-[1,4 ′] bipiperidyl,
1- {2- [5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] pyrid-2-yl) indol-1-yl] ethyl} piperid-3-ol,
2- {5,6-dimethoxy-1- [2- (4-methylperhydro-1,4-diazepin-1-yl) ethyl] -1H-indol-3-yl} -1H-pyrrolo [2,3 -B] pyridine,
2- [5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] pyrid-2-yl) indol-1-yl] -1- (4-hydroxypiperidin-1-yl) ethanone,
2- [5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] pyrid-2-yl) indol-1-yl] -1-thiazolidin-3-ylethanone,
4-{[5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] pyrid-2-yl) indol-1-yl] acetyl} -1-methylpiperazin-2-one,
4-chloro-2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyridine,
2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyridine-4-carbonitrile,
4-chloro-2- [5,6-dimethoxy-1- (2-morpholin-4-ylethyl) -1H-indol-3-yl] -1H-pyrrolo [2,3-b] pyridine,
2- (1- {2- [3- (4-Chloro-1H-pyrrolo [2,3-b] pyrid-2-yl) -5,6-dimethoxyindol-1-yl] ethyl} piperidi-4- Yl) ethanol,
4-chloro-2- {5,6-dimethoxy-1- [2- (4-methylpiperazin-1-yl) -ethyl] -1H-indol-3-yl} -1H-pyrrolo [2,3-b ] Pyridine,
2- {5,6-dimethoxy-1- [2- (4-methylpiperazin-1-yl) ethyl] -1H-indol-3-yl} -1H-pyrrolo [2,3-b] pyridine-4- Carbonitrile,
2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -5-fluoro-1H-pyrrolo [2,3-b] pyridine,
2- [5,6-dimethoxy-1- (2-morpholin-4-ylethyl) -1H-indol-3-yl] -5-fluoro-1H-pyrrolo [2,3-b] pyridine,
2- {5,6-dimethoxy-1- [2- (4-methylpiperazin-1-yl) ethyl] -1H-indol-3-yl] -5-fluoro-1H-pyrrolo [2,3-b] Pyridine,
2- [5-methoxy-1-methyl-3- (1H-pyrrolo [2,3-b] pyrid-2-yl) -1H-indol-6-yloxy] -1-morpholin-4-ylethanone,
2- [5-Methoxy-1-methyl-3- (1H-pyrrolo [2,3-b] pyrid-2-yl) -1H-indol-6-yloxy] -1- (4-methyl [1,4 ] Diazepan-1-yl) ethanone,
2- [5-Methoxy-1-methyl-3- (1H-pyrrolo [2,3-b] pyrid-2-yl) -1H-indol-6-yloxy] -N- [4- (4-methylpiperazine -1-yl) phenyl] aceto-amide,
2- [5-Methoxy-1-methyl-3- (1H-pyrrolo [2,3-b] pyrid-2-yl) -1H-indol-6-yloxy] -1- (4-methylpiperazine-1- Il) Ethanon,
1- {4- [2- (2-hydroxyethoxy) ethyl] piperazin-1-yl} -2- [5-methoxy-1-methyl-3- (1H-pyrrolo [2,3-b] pyrid-2 -Yl) -1H-indol-6-yloxy] ethanone,
(3aS, 6aS) -5- {2- [5-Methoxy-1-methyl-3- (1H-pyrrolo [2,3-b] -pyrid-2-yl) -1H-indol-6-yloxy] acetyl } Hexahydropyrrolo [3,4-c] pyrrol-1-one trifluoroacetate,
2- {5-Methoxy-1-methyl-6- [3- (4-methylperhydro-1,4-diazepin-1-yl) propoxy] -1H-indol-3-yl} -1H-pyrrolo [2 , 3-b] pyridine,
4-Chloro-2- {1-methyl-5-methoxy-6- [2- (4-methylpiperazin-1-yl) ethoxy] -1H-indol-3-yl} -1H-pyrrolo [2,3- b] pyridine,
4-chloro-2- {1-methyl-5-methoxy-6- [2- (4-piperidylpiperid-1-yl) ethoxy] -1H-indol-3-yl} -1H-pyrrolo [2,3 -B] pyridine,
4-Chloro-2- {5-methoxy-1-methyl-6- [2- (2-pyrrolidineethyl-amino) ethoxy] -1H-indol-3-yl} -1H-pyrrolo [2,3-b] Pyridine,
4-chloro-2- {1-methyl-5-methoxy-6- [2- (2-piperidineethyl-amino) ethoxy] -1H-indol-3-yl} -1H-pyrrolo [2,3-b] There is a product of formula (I) as defined above which is of pyridine
The product of formula (I) is a racemic, enantiomeric or diastereomeric isomer form, and addition salts of the product of formula (I) with inorganic and organic acids or with inorganic and organic bases. May be.

Among the preferred manufactured articles of the present invention, mention may be made in more detail of the name:
2- {5,6-dimethoxy-1- [2- (4-methylpiperazin-1-yl) ethyl] -1H-indol-3-yl} -1H-pyrrolo [2,3-b] pyridine,
2- (4- {2- [5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] pyridin-2-yl) indol-1-yl] ethyl} piperazin-1-yl) ethanol,
2- (1- {2- [5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] pyridin-2-yl) indol-1-yl] ethyl} piperidin-4-yl) ethanol,
1 ′-{2- [5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] pyridin-2-yl) indol-1-yl] ethyl}-[1,4 ′] bipiperidinyl,
1- {2- [5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] pyridin-2-yl) -indol-1-yl] ethyl} piperidin-3-ol,
2- {5,6-dimethoxy-1- [2- (4-methylperhydro-1,4-diazepin-1-yl) ethyl] -1H-indol-3-yl} -1H-pyrrolo [2,3 -B] pyridine,
2- [5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] pyridin-2-yl) indol-1-yl] -1- (4-hydroxypiperidin-1-yl) ethanone,
2- [5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] pyridin-2-yl) indol-1-yl] -1-thiazolidin-3-ylethanone,
4-{[5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] pyridin-2-yl) indol-1-yl] acetyl} -1-methylpiperazin-2-one,
4-chloro-2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyridine,
2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyridine-4-carbonitrile,
4-chloro-2- [5,6-dimethoxy-1- (2-morpholin-4-ylethyl) -1H-indol-3-yl] -1H-pyrrolo [2,3-b] pyridine,
2- (1- {2- [3- (4-Chloro-1H-pyrrolo [2,3-b] pyridin-2-yl) -5,6-dimethoxyindol-1-yl] ethyl} piperidine-4- Yl) ethanol,
4-Chloro-2- {5,6-dimethoxy-1- [2- (4-methylpiperazin-1-yl) ethyl] -1H-indol-3-yl} -1H-pyrrolo [2,3-b] Pyridine,
2- {5,6-dimethoxy-1- [2- (4-methylpiperazin-1-yl) ethyl] -1H-indol-3-yl} -1H-pyrrolo [2,3-b] pyridine-4- Carbonitrile,
2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -5-fluoro-1H-pyrrolo [2,3-b] pyridine,
2- [5,6-dimethoxy-1- [2-morpholin-4-ylethyl) -1H-indol-3-yl] -5-fluoro-1H-pyrrolo [2,3-b] pyridine,
2- {5,6-dimethoxy-1- [2- (4-methylpiperazin-1-yl) ethyl] -1H-indol-3-yl} -5-fluoro-1H-pyrrolo [2,3-b] Pyridine,
2- [5-methoxy-1-methyl-3- (1H-pyrrolo [2,3-b] pyridin-2-yl) -1H-indol-6-yloxy] -1-morpholin-4-ylethanone,
2- [5-Methoxy-1-methyl-3- (1H-pyrrolo [2,3-b] pyridin-2-yl) -1H-indol-6-yloxy] -1- (4-methyl- [1, 4] diazepan-1-yl) ethanone,
2- [5-Methoxy-1-methyl-3- (1H-pyrrolo [2,3-b] pyridin-2-yl) -1H-indol-6-yloxy] -N- [4- (4-methylpiperazine) -1-yl) phenyl] acetamide,
2- [5-Methoxy-1-methyl-3- (1H-pyrrolo [2,3-b] pyridin-2-yl) -1H-indol-6-yloxy] -1- (4-methylpiperazine-1- Il) Ethanon,
1- {4- [2- (2-hydroxyethoxy) ethyl] piperazin-1-yl} -2- [5-methoxy-1-methyl-3- (1H-pyrrolo [2,3-b] pyridine-2 -Yl) -1H-indol-6-yloxy] ethanone,
(3aS, 6aS) -5- {2- [5-Methoxy-1-methyl-3- (1H-pyrrolo- [2,3-b] pyridin-2-yl) -1H-indol-6-yloxy] acetyl } Hexahydro-pyrrolo [3,4-c] pyrrol-1-one trifluoroacetate 2- {5-methoxy-1-methyl-6- [3- (4-methylperhydro-1,4-diazepine- 1-yl) propoxy] -1H-indol-3-yl} -1H-pyrrolo- [2,3-b] pyridine,
4-chloro-2- {1-methyl-5-methoxy-6- [2- (4-methylpiperazin-1-yl) ethoxy-1H-indol-3-yl} -1H-pyrrolo [2,3-b ] Pyridine,
4-chloro-2- {1-methyl-5-methoxy-6- [2- (4-piperidyl-piperidin-1-yl) ethoxy-1H-indol-3-yl} -1H-pyrrolo [2,3- b] -pyridine,
4-Chloro-2- {5-methoxy-1-methyl-6- [2- (2-pyrrolidineethyl-amino) ethoxy] -1H-indol-3-yl} -1H-pyrrolo [2,3-b] Pyridine,
4-chloro-2- {1-methyl-5-methoxy-6- [2- (2-piperidineethylamino) ethoxy-1H-indol-3-yl} -1H-pyrrolo [2,3-b] pyridine There is a product of formula (I) as defined above which is
The product of formula (I) is a racemic, enantiomeric or diastereomeric isomer form, and addition salts of the product of formula (I) with inorganic and organic acids or with inorganic and organic bases. May be.

  One subject of the present invention is also a process for producing the product of formula (I) above. The product of formula (I) of the present invention described above can be prepared according to the methods shown in Schemes 1-6 described below. These diagrams thus illustrate the steps in the synthesis of the product of formula (I) of the present invention and are part of the present invention.

  Thus, Scheme 1 illustrates route “A” for obtaining the derivative of formula (I): 2- (1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyridine. .

  Thus, Scheme 2 illustrates route “B” in obtaining the derivative of formula (I): 2- (Indol-3-yl) -1H-pyrrolo [2,3-b] pyridine.

  Schemes 3 and 4 illustrate the pathway for introducing a substituent at the R1 position and the pathway for introducing a substituent at the R3 position, respectively, in the synthesis of the product of formula (I) of the present invention.

  1H-pyrrolo [2,3-b] pyridines of formula 1 according to the invention:

（式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５、Ｒ６およびＲは上記で定義の通りである。）は、添付資料における図式１〜４に従って製造することができ、それらの図式は本発明の一部である。

(Wherein R1, R2, R3, R4, R5, R6 and R are as defined above) can be prepared according to Schemes 1-4 in the accompanying material, and those schemes are It is a part.

In Scheme 1, more specifically, for example, acetic acid or the like at a temperature of 20 ° C. to 80 ° C. under the conditions described by Hus et al. (Fuss and V. Koch, Synthesis, 1990, 8, 681-5). Treatment of 2-aminopyridines of formula (A) wherein R ₅ is other than H in a solvent with N-iodosuccinimide or N-bromosuccinimide, results in 3-halo-2-amino of formula (B) Pyridine is obtained.

  More specifically, 3-trimethylsilanylethynylpyridin-2-ylamines of the formula (C) can be obtained at temperatures of 20 ° C. to 120 ° C. in a solvent such as dimethylformamide [1,1′-bis (diphenylphosphine). Fino) ferrocene] palladium (II) chloride or a catalyst such as bis (triphenylphosphine) palladium (II) chloride, a base such as copper iodide, triethylamine and optionally lithium chloride, and optionally 3- Using halo-2-aminopyridines, for example, ethinyltrimethylsilane and Sonogashira-type coupling can be performed under the conditions described by Noher et al. (P. Knochel et al., Tetrahedron, 2003, 59, 1571-1587). It can be obtained by doing.

  More specifically, the 1H-pyrrolo [2,3-b] pyridines of the above formula (D) can be obtained by using potassium tert-butoxide in a solvent such as 1-methyl-2-pyrrolidinone at a temperature of 20 ° C. to 120 ° C. Alternatively, it can be obtained by cyclizing the derivative of formula (C) in the presence of a strong base such as potassium hydride.

More specifically, the 1H-pyrrolo [2,3-b] pyridine 7-oxides of formula (E) are prepared under the conditions described in patent WO 03 / 000688A1 at temperatures around 20 ° C. and 1,2-dimethoxyethane. It can obtain by treating the derivative of the formula (D1) with 3-chloroperbenzoic acid in an ether solvent such as. 1H-pyrrolo [2,3-b] pyridines of the formula (D) in which R ₄ = Cl is treated with phosphorous oxychloride at a temperature of 20 ° C. to 50 ° C. to give 1H— of the formula (E) It can be obtained from pyrrolo [2,3-b] pyridine 7-oxides.

  More particularly, 1H-pyrrolo [2,3-b] pyridines of the formula (F) are a mixture of water and a solvent such as toluene at a temperature around 20 ° C. under the conditions described in patent WO 03 / 000688A1. Medium by treatment with the corresponding sulfonyl chloride in the presence of a strong base such as sodium hydroxide and a quaternary ammonium salt such as tetrabutylammonium hydrogensulfate, for example with a group such as p-toluenesulfonyl or benzenesulfonyl. It can be obtained by protecting the nitrogen atom of the derivative of D).

  1H-pyrrolo [2,3-b] pyridines of the formula (G) can be obtained by using n-butyllithium or tert-butyl ether in an ether solvent such as tetrahydrofuran at a temperature around −78 ° C. under the conditions described in the above patent. It can be obtained by treating the derivative of formula (F) with a strong base such as butyl lithium and then adding an iodine solution in a solvent such as tetrahydrofuran.

More specifically, 1H-pyrrolo [2,3-b] pyridines of the formula (F) where R ₄ = I and GP = acetyl are reported by Allegretti et al. (M. Allegretti et al., Synlett, 2001, 5, 609-612) by treatment with acetyl chloride in a solvent such as acetonitrile in the presence of sodium iodide at a temperature from 20 ° C. to the reflux temperature of the solvent, so that R ₄ = Cl It can be prepared from 1H-pyrrolo [2,3-b] pyridines of certain formula (D).

By treatment in a solvent such as methanol at a temperature from 20 ° C. to the reflux temperature of the solvent under the conditions described in the above documents, 1 H-pyrrolo of the formula (F) in which R ₄ = I and GP = acetyl [ From 2,3-b] pyridines, derivatives of formula (D) where R ₄ = I can be obtained.

More specifically, 1H-pyrrolo [2,3-b] pyridines of the formula (F1) are stannic derivatives such as tetramethyltin in a solvent such as dimethylformamide at a temperature of 20 ° C. to 120 ° C. In the presence of a catalyst such as bis (triphenylphosphine) palladium (II) chloride and a phosphine such as lithium chloride or triphenylphosphine (Javier Form et al., Synth Commun , 23 (21), 2965, 1993) can be prepared from derivatives of formula (F) where R ₄ = I.

  More particularly, 1H-indoles of the formula (I) are prepared under the conditions described in patent WO 03 / 000688A1 with strong bases such as potassium hydroxide and organic bases such as 4- (dimethylamino) -pyridine. It can be obtained from the derivative of formula (H) by treatment with iodine in the presence and then addition of di-tert-butyl dicarbonate in a solvent such as dimethylformamide at a temperature of 20 ° C to 60 ° C.

  More specifically, 1H-indoles of formula (J) can be obtained in ether-based solvents such as tetrahydrofuran, for example N-butyllithium, under the conditions described in patent WO03 / 000688A1, at temperatures of −100 ° C. to 20 ° C. Can be prepared from derivatives of formula (I) by treatment with a strong base such as, for example, and a boronic ester such as tributyl borate.

  More specifically, 1H-pyrrolo [2,3-b] pyridines of the formula (K) can be obtained by using, for example, dimethylformamide at a temperature from 20 ° C. to the reflux temperature of the solvent under the conditions described in Patent WO 03 / 000688A1. In the presence of a catalyst such as tetrakis (triphenyl-phosphine) palladium and a base such as an aqueous solution of sodium hydrogensulfate by Suzuki coupling of a derivative of formula (J) with a derivative of formula (G). be able to.

  In Scheme 2, in more detail, dimethylformamide and the like can be obtained at a temperature around 20 ° C. under the conditions described in the report of Gribble (Gordon W. Gribble, J. Nat. Prod, 2002, 65, 748-749). Treatment of 1H-indoles of formula (H) with a strong base such as potassium hydroxide in a solvent, followed by addition of iodine or bromine, followed by addition of, for example, an alkyl halide (preferably methyl iodide). To give 3-halo-1H-indoles of the formula (N).

  3- (Trimethylsilanylethynyl-1H-indoles of formula (O) can be prepared from derivatives of formula (N) by Sonogashira-type coupling under the conditions described above for derivatives of formula (C). .

  3-Ethynyl-1H-indoles of the formula (P) are, for example, potassium fluoride in a solvent such as methanol or tetrabutylammonium fluoride in a solvent such as tetrahydrofuran at a temperature from 20 ° C. to the reflux temperature of the solvent. Obtained by treatment of the derivative of formula (O) by treatment with a fluorine derivative.

  More specifically, 3-ethynylpyridin-2-ylamines of formula (L) can be obtained from derivatives of formula (C) under the conditions described above for derivatives of formula (P).

More particularly, the 3- (1H-indole-3-ethynyl) pyridin-2-ylamines of formula (M) are
Between 3-halo-2-aminopyridines of formula (B) and 3-ethynyl-1H-indoles of formula (P), or 3-halo-1H-indoles of formula (N) and formula It can be obtained by Sonogashira type coupling between (L) and 3-ethynylpyridin-2-ylamines.

  1H-pyrrolo [2,3-b] pyridines of Formula 1 can be obtained at 20 ° C. to 120 ° C. under the conditions described in Noher et al. (P. Knochel et al., Tetrahedron, 2003, 59, 1571-1587). It can be produced by treating the derivative of formula (M) with a strong base such as potassium tert-butoxide or potassium hydride in a solvent such as 1-methyl-2-pyrrolidinone at a temperature of ° C.

In Scheme 3, more particularly, 1H-pyrrolo [2,3-b] pyridines of formula (Q) are sodium hydride in a solvent such as dimethylformamide at a temperature of, for example, 20 ° C. to the reflux temperature of the solvent. In the presence of a base such as Ergen et al. (D. Oelgen et al., Pharmazie, 57 (4), 238, 2002)
-Cyclic or acyclic optionally substituted amines,
Halogen (thus giving a derivative of formula (Q2)),
An alkoxy group, thereby giving a derivative of formula (Q3),
An alkoxycarbonyl group, thereby giving a derivative of formula (Q4)
The terminal group can be obtained by alkylating the derivative of formula (K) with an alkyl halide which may be substituted.

  In the case of the derivative of formula (Q2), Bogdal et al. Reported in dichloroethane in the presence of a base such as quaternary ammonium such as potassium hydroxide, potassium carbonate and tetrabutylammonium bromide at a temperature around 20 ° C. (D Bogdal et al., Synthetic Communication, 30 (18), 3341-3352, 2000) may be used.

Alternatively, 1H-pyrrolo [2,3-b] pyridine formula (Q4) where R ′ ₁ = 2- (CH ₂ ) ₂ CO ₂ tBu can be obtained by reacting dimethylformamide at a temperature from 20 ° C. to the reflux temperature of the solvent, for example. In the presence of a base such as potassium carbonate in a solvent such as, under the conditions described in Lady et al. (MVR Reddy et al., J. Org. Chem, 67 (15), 5382, 2002) It can be obtained by alkylating a derivative of K) with tert-butyl acrylate.

  More specifically, 1H-pyrrolo [2,3-b] pyridines of the formula (1a) are present in the presence of a base such as potassium hydroxide in a solvent such as methanol at a temperature of, for example, 20 ° C. to the reflux temperature of the solvent. Below, the p-toluenesulfonyl group and the ester of the derivative of formula (Q4) were simultaneously removed under the conditions described in the report of Samet et al. (AV Samet et al., Synth Commun, 31 (9), 1441, 2001). It can be obtained by protecting it.

More specifically, the 1H-pyrrolo [2,3-b] pyridines of the formula (1) in which R ₁ = (CH ₂ ) _n CONR ₇ R ₈ are described in, for example, Dotgrow et al. (V. Dourtoglou and B. Gross, Synthesis, 572, 1984) under conditions such as O-benzotriazolyl-N, N, N ', N'- in a solvent such as dimethylformamide at a temperature from 20 ° C to the reflux temperature of the solvent. Peptide couplings such as tetramethyluronium hexafluorophosphate (HBTU) or O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HAUT) It can be obtained by amidating the derivative of formula (1a) with amine HNR ₇ R ₈ using an agent.

  More specifically, 1H-pyrrolo [2,3-b] pyridines of the formula (R) are described in, for example, a report by Allen et al. (CFH Allen et al., J. Org Chem, 14, 754, 1949). Under the conditions, it can be obtained by reacting the derivative of the formula (Q2) with sodium iodide or potassium iodide in a solvent such as methyl ethyl ketone at a temperature from 20 ° C. to the reflux temperature of the solvent.

More specifically, 1H-pyrrolo [2,3-b] pyridines of the formula (S) are described, for example, by Pujol et al. (MD Pujol et al., Eur. J. Med. Chem., 31 (11), 889, 1996) in the presence of a base such as potassium carbonate in a solvent such as methyl ethyl ketone at a temperature between 20 ° C. and the reflux temperature of the solvent, and the amine HNR ₇ R ₈ It can be obtained by reacting with.

  More specifically, 1H-pyrrolo [2,3-b] pyridines of the formula (U) or (T) are described, for example, by Jin et al. (Fuqiang Jin et al., Tetrahedron Letters 41, 2000, 3271-3273). In the presence of a catalyst such as zinc and 1,1′-bis (diphenylphosphino) ferrocenepalladium (II) dichloride in a solvent such as dimethylacetamide at a temperature of 20 ° C. to 150 ° C. In addition, it can be obtained from 4-chloro-1H-pyrrolo [2,3-b] pyridines of the formula (Q1) or (S1) by the action of zinc cyanide.

  In more detail, 1H-pyrrolo [2,3-b] pyridines of the formula (V) are described, for example, by Buckwald et al. (L. Buchwald et al., J. Org. Chem, 61, 1996, 7240- 7241) at a temperature between 20 ° C. and the reflux temperature of the solvent, in a solvent such as toluene, in a solvent such as cesium carbonate, a catalyst such as palladium (II) acetate and, for example, 2,2′bis (diphenylphosphine). It can be obtained from the derivative of formula (Q1) by backwald coupling with benzophenone imine in the presence of ligands such as fino) -1,1′-binaphthyl.

  1H-pyrrolo [2,3-b] pyridines of the formula (W) are obtained under conventional conditions described in Green et al. (Greene and Wuts in Protective Groups in Organic Synthesis, 3rd edition, Wiley-Interscience). It can be obtained from the derivative of formula (V) by hydrolysis of imine in a solvent such as tetrahydrofuran in an acid medium, for example aqueous hydrochloric acid, at a temperature from 20 ° C. to the reflux temperature of the solvent.

More specifically, 1H-pyrrolo [2,3-b] pyridines of formula (X) with Φ = OH are described, for example, by Corey et al. (EJ Corey and A. Venkateswarlu, J Am Chem Soc, 94, 6190). , under the conditions described in 1972), at a temperature and the reflux temperature of the solvent 20 ° C., in a solvent such as tetrahydrofuran, for example by reaction with a fluoro derivatives, such as tetrabutylammonium _{fluoride, R '1 = (CH 2} ) _n OSiMe ₂ tBu [(CH ₂ ) _n OTBDMS] can be obtained from the derivative of formula (Q3). During this reaction, derivatives of formula (X) where Φ = F are also obtained.

  More specifically, 1H-pyrrolo [2,3-b] pyridines of formula (1) are described in Green et al. (Greene and Wuts, Protective Groups in Organic Synthesis, 3rd edition, Wiley-Interscience, 1999). Can be obtained by deprotecting the derivatives of formulas (S), (T), (U), (W), (X) and (Q).

  When the protecting group is a p-toluenesulfonyl group, N-deprotection of the derivatives of formula (S), (T), (U), (W), (X) and (Q) can be carried out, for example by formula (1a) In the presence of tetrabutylammonium fluoride in a solvent such as tetrahydrofuran at a temperature from 20 ° C. to the reflux temperature of the solvent, for example.

  In Scheme 4, more particularly, 1H-pyrrolo [2,3-b] pyridines of formula (Q5) are obtained from derivatives of formula (K1) according to the methods described above for derivatives of formula (Q). Can do.

  More specifically, the 1H-pyrrolo [2,3-b] pyridines of the formula (Y) are prepared under the conditions described in, for example, the report of Jun et al. (ME Jung and MA Lyster, J Org Chem, 42, 3761, 1977). Below, the derivative of formula (Q5) can be benzylated in the presence of trimethylsilane iodide in a solvent such as acetonitrile at a temperature from 20 ° C. to the reflux temperature of the solvent.

More specifically, 1H-pyrrolo [2,3-b] pyridine derivatives of formula (Z) where Σ = CO-alkyl are described, for example, by Gonzalez-Gomez et al. (JC Gonzalez-Gomez et al., Bioorg Med. Chem. Letters, 12, (2), 175, 2003) in the presence of a base such as sodium hydride in a solvent such as dimethylformamide at a temperature from 20 ° C. to the reflux temperature of the solvent. It can be obtained by reacting a derivative of formula (Y) with a substituted alkyl halide such as X (CH ₂ ) _n OCO-alkyl.

  More specifically, 1H-pyrrolo [2,3-b] pyridines of formula (1) where Σ = H are, for example, Σ = CO-alkyl under the conditions described above for the derivatives of formula (1a) It can be obtained by simultaneous deprotection of a certain (Y) p-toluenesulfonyl group and ester group.

Alternatively, 1H-pyrrolo [2,3-b] pyridines of the formula (Z) where Σ = alkyl are described, for example, by Leshot et al. (A. Leschot et al., Synth Commun, 32 (20), 3219, under the conditions described in 2002), at a temperature and the reflux temperature of the solvent 20 ° C., acetone, in a solvent such as acetonitrile or dimethylformamide, in the presence of a base such as cesium carbonate or potassium carbonate, X (CH _{2) n} It can be obtained by reacting an alkyl ether halide such as O-alkyl with a derivative of the formula (Y).

Alternatively, 1H-pyrrolo [2,3-b] pyridines of formula (Z) where Σ = (CH ₂ ) _n Cl are, for example, the conditions described above for derivatives of formula (Z) where Σ = CO-alkyl. And a derivative of formula (Y) can be obtained by reacting with a dialkyl ether dihalide such as X (CH ₂ ) _n O— (CH ₂ ) _n X.

Alternatively, 1H-pyrrolo [2,3-b] pyridines of the formula (Z) where Σ = (CH ₂ ) _n NR ₇ R ₈ are, for example, under the conditions described above for derivatives of formula (S), Σ = It can be obtained by reacting a derivative of formula (Z) that is (CH ₂ ) _n Cl with amine HNR ₇ R ₈ .

  More particularly, 1H-pyrrolo [2,3-b] pyridines of the formula (AA) in which GP = p-toluenesulfonyl are the conditions described above for derivatives of the formula (Z) in which, for example, Σ═CO-alkyl. Below, it can be obtained by alkylating a derivative of formula (Y) with an alkyl halide.

  More specifically, the 1H-pyrrolo [2,3-b] pyridines of formula (1b) can be prepared, for example, under the conditions described above for the derivatives of formula (1a) with p-toluenesulfonyl and ester groups of (AA). It can be obtained by deprotecting at the same time.

More specifically, 1H-pyrrolo [2,3-b] pyridines of the formula (1) in which R ₃ = OCH ₂ CONR ₇ R ₈ are described in, for example, literature (“Practical Guide to Combinatorial Chemistry”, ISBN 0-8412. -3485-x, p-51-97) in the presence of dicyclohexylcarbodiimide or hydroxyazabenzotriazole and a base in a solvent such as dimethylformamide at a temperature from 20 ° C. to the reflux temperature of the solvent under the conditions described in It can be obtained by amidating a derivative of formula (1b) with amine HNR ₇ R ₈ .

  More specifically, the 6-hydroxy-1H-pyrrolo [2,3-b] pyridines of formula (AB) desorb the derivatives of formula (K1), for example under the conditions described above for the derivatives of formula (Y). It can be obtained by benzylation.

  More particularly, 1H-pyrrolo [2,3-b] pyridines of the formula (AC) in which GP = p-toluenesulphonyl are represented by the formula (AB), for example, under the conditions described above for the derivatives of formula (AA). Can be obtained by bisalkylation with an alkyl acetate halide.

  More specifically, 1H-pyrrolo [2,3-b] pyridines of the formula (AD) are described in, for example, Parker et al. (KA Parker and QJ Ding, Tetrahedron, 56 (52), 10249, 2000). Under the conditions, it can be obtained by reacting the derivative of formula (Y) with triflic anhydride in the presence of a base such as pyridine in a solvent such as methylene chloride at a temperature from 0 ° C. to the reflux temperature of the solvent. .

  More specifically, 1H-pyrrolo [2,3-b] pyridines of the formula (AE) are prepared under the conditions described in, for example, the report of Cockerill (GS Cockerill, J Chem Soc, Perkin Trans. 1, 2591, 2000). And a derivative of formula (AD) in the presence of a catalyst such as tetrakis (triphenylphosphine) palladium and a base such as aqueous sodium hydrogen carbonate in a solvent such as dimethylformamide at a temperature from 20 ° C. to the reflux temperature of the solvent. It can be obtained by Suzuki-type coupling between alkylboronic acids.

  More specifically, 1H-pyrrolo [2,3-b] pyridines of formula (AF) can be converted to alkyl dihalide derivatives of formula (Y), for example, under the conditions described above for derivatives of formula (AA). Can be obtained.

  More specifically, 1H-pyrrolo [2,3-b] pyridines of formula (AG) are obtained by halogen exchange from derivatives of formula (AF), for example under the conditions described above for derivatives of formula (R). be able to.

More specifically, 1H-pyrrolo [2,3-b] pyridines of formula (AH) can be converted to amine HNR ₇ R ₈ under the conditions described above, for example with respect to derivatives of formula (S). It can be obtained by reacting with.

  More specifically, 1H-pyrrolo [2,3-b] pyridines of formula (1) are described in Green et al. (Greene and Wuts, Protective Groups in Organic Synthesis, 3rd edition, Wiley-Interscience, 1999). Can be obtained by deprotecting the derivatives of formula (AC), (AE), (AH) and (Z).

  When the protecting group is a p-toluenesulfonyl group, deprotection of the derivatives of formula (AC), (AE), (AH) and (Z) is carried out under the conditions described above, for example with respect to the derivative of formula (1a).

  Scheme 5 illustrates a synthetic route for obtaining 2- (1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyridine-4-carboxaldehyde derivatives.

  More specifically, for example, under the conditions described in Anderson et al. (Anderson, BA et al., J. Org. Chem., 1997, 62 (25), 8634-8639), a temperature of −30 ° C. to 20 ° C. Treating 4-cyano-1H-pyrrolo [2,3-b] pyridines of general formula (AI) with a reducing agent such as aluminum diisobutyl hydride (DIBAH) in an aprotic solvent such as toluene at temperature. To give 4-carboxy-aldehyde-1H-pyrrolo [2,3-b] pyridines of general formula (AJ).

  More specifically, 4- (1,3-dioxolane) -1H-pyrrolo [2,3-b] pyridines of general formula (AK) are described, for example, by Pasto et al. (Pasto M. et al., Tetrahedron: Asymmetry, 1995, 6 (9), 2329-2342) at a temperature of 80 ° C. to 120 ° C. in the presence of an acidic catalyst such as para-toluenesulfonic acid in a solvent such as toluene. It can be obtained by reacting the derivative of the general formula (AJ) with ethylene glycol.

  4- (1,3-Dioxolane) -2-iodo-1H-pyrrolo [2,3-b] pyridines of the general formula (AL) are produced under the conditions described in Patent WO03 / 000688A1 at around -78 ° C. Treat the derivative of general formula (AK) with a strong base such as n-butyllithium or tert-butyllithium in an ether solvent such as tetrahydrofuran at temperature and then add iodine as a solution in a solvent such as tetrahydrofuran Can be obtained.

  More specifically, the 1H-pyrrolo [2,3-b] pyridines of general formula (AM) can be prepared according to the methods described above for derivatives of general formula (K) and derivatives of general formula (J) and general formulas It can be obtained by Suzuki coupling with a derivative of (AL).

  More specifically, 1H-pyrrolo [2,3-b] pyridines of general formula (AN) can be obtained from derivatives of general formula (AM) according to the methods described above for derivatives of general formula (Q). .

  In more detail, 1H-pyrrolo [2,3-b] pyridines of the general formula (AO) are described in, for example, a report by Ishimaru et al. (Ishimaru K. et al., Heterocycles, 2001, 55 (8), 1591-1597 The derivative of the general formula (AN) can be obtained by treating the derivative of the general formula (AN) in the presence of an acid such as hydrochloric acid in a solvent such as tetrahydrofuran at a temperature of 20 ° C. to 60 ° C.

  Scheme 6 illustrates a synthetic route for introducing substituent R4 into the product of formula (I).

  More specifically, 1H-pyrrolo [2,3-b] pyridines of the general formulas (AP) and (AP2) are described, for example, by Patra et al. (Patra, PK et al., Eur. J. Org. Chem. , 2001, 22, 4195-4206) in the presence of a hydride such as sodium borohydride and a dehydrating agent such as magnesium sulfate in a solvent such as methanol or ethanol at a temperature around 20 ° C. The derivative of general formula (AO) can be obtained by treating with an amine.

These 1H-pyrrolo [2,3-b] pyridines of the general formula (AP) are
For example, under the conditions described in a report by Kaneko et al. (Kaneko, T. et al., Chem. Pharm. Bull., 2002, 50 (7), 922-929), acetonitrile at a temperature from 20 ° C. to the boiling point of the solvent. By treating a derivative of the general formula (AR) with a halide or mesylate in the presence of a base such as sodium carbonate in a solvent such as, or at a temperature between 20 ° C. and the boiling point of the solvent, for example, under the conditions described above. It can also be obtained by treating the derivative of general formula (AU) with an amine in the presence of a base such as sodium carbonate in a solvent such as acetonitrile.

  1H-pyrrolo [2,3-b] pyridines of the general formula (AQ) are, for example, reported by Schroeder et al. (Schroeder, MC et al., J. Heterocyclic Chem., 1992, 29 (6), 1481-1498 ) By treating 1H-pyrrolo [2,3-b] pyridine of the general formula (AO) with hydroxylamine hydrochloride in a solvent such as pyridine at a temperature of 20 ° C. to 50 ° C. Obtainable.

  More specifically, 4-aminomethyl-1H-pyrrolo [2,3-b] pyridines of the general formula (AR) are described, for example, by Prasitpan et al. (Prasitpan, N. et al., Synth. Commun., 1990). 20 (22), 3459-3466) with a metal such as zinc in a solvent such as water and / or ethanol in the presence of an acid such as acetic acid or formic acid at a temperature around 20 ° C. It can be obtained by reducing oxime (AQ).

  More specifically, 1H-pyrrolo [2,3-b] pyridines of the general formula (AS) are reported by Metz et al. (Metz, P. et al., Synlett, 1996, (8), 741-742). (Hergueta, AR et al., Chem. Pharm. Bull., 2002, 50 (10), 1379-1382) and Koelho et al. (Coelho, PJ et al., Synlett, 2001, (9 ), 1455-1457), the derivative of general formula (AR) is substituted in the presence of a base such as triethylamine in an aprotic solvent such as methylene chloride at a temperature of 0 ° C. to 20 ° C. It can be obtained by treating with sulfonyl chlorides, substituted isocyanates or substituted acid chlorides.

  The 1H-pyrrolo [2,3-b] pyridine-4-methanol compound of the general formula (AT) is, for example, reported by Wang et al. (Wang, EC et al., Heterocycles, 2002, 57 (11), 2021-2033). Can be obtained by reducing a derivative of the general formula (AO) with a hydride such as sodium borohydride in an ether solvent such as tetrahydrofuran at a temperature around 20 ° C.

  More specifically, 1H-pyrrolo [2,3-b] pyridines of the general formula (AU) where X = Cl are reported by Fucase et al. (Fucase K. et al., Tetrahedron Lett., 1991, 32 ( 32), 4019-4022), by treatment with thionyl chloride in the presence of DMF in a solvent such as methylene chloride at a temperature of 0 ° C. to 20 ° C. It can be obtained from 1H-pyrrolo [2,3-b] pyridine-4-methanol compound.

1H-pyrrolo [2,3-b] pyridines of the general formula (AU) where X = OSO ₂ Me are reported by Altamura et al. (Altamura M. et al., J. Org. Chem., 1993, 58 ( 1), 272-274), by treatment with methanesulfonic anhydride in the presence of a base such as pyridine in a solvent such as methylene chloride at a temperature of −10 ° C. to 20 ° C. It can be obtained from 1H-pyrrolo [2,3-b] pyridine-4-methanol compound of general formula (AT).

  In more detail, 1H-pyrrolo [2,3-b] pyridines of the general formula (AV) are represented by Labrosse, JR et al., Synth. Commun., 2002, 32 (23), 3667-3674). Can be obtained by treating the derivative of the general formula (AO) with a Grignard reagent in a solvent such as tetrahydrofuran at a temperature of 0 ° C to 20 ° C.

  More specifically, 1H-pyrrolo [2,3-b] pyridines of the general formula (AW) where B = CORa, CONHRb, SO2Rc are those of the general formula (AP2) described above with respect to the derivatives of the general formula (AS). It can be obtained from a derivative.

  More specifically, 1H-pyrrolo [2,3-b] pyridines of the general formula (AX) are described in Green et al. (Greene and Wuts, Protective Groups in Organic Synthesis, 3rd edition, Wiley-Interscience, 1999). It can be obtained by deprotecting the derivative of general formula (AW) under the standard conditions described.

  More specifically, 1H-indoles of the general formula (1) are obtained under the conditions described in Mader et al. (Madar, DJ, et al., Tetrahedron Lett., 2001, 42, 3681-3684). It can be obtained from the derivative of the general formula (AX) by treatment with an acid such as trifluoroacetic acid or para-toluenesulfonic acid in a solvent such as methylene chloride or toluene at a temperature of -100 ° C.

  More specifically, 1H-pyrrolo [2,3-b] pyridines of general formula (1) are described in Green et al. (Greene and Wuts, Protective Groups in Organic Synthesis, 3rd edition, Wiley-Interscience, 1999). It can be obtained by deprotecting a derivative of the general formula (AP), (AQ), (AR), (AS) or (AV) under the standard conditions described.

One subject of the present invention includes:
A process for the preparation of the product of general formula (D) and most particularly a reaction with 2-aminopyridines (A) according to scheme 1;
-There is also a process for the preparation of the product of general formula (1) and most particularly the reaction according to scheme 2.

  It should be noted that the intermediate product or the product of formula (I) is optionally used in the reaction for producing the product of formula (I) according to the present invention, particularly in the reaction shown in the diagram. The functional group that may react may be protected with a protecting group.

  For intermediate products or products of formula (I), which may be in protected or unprotected form, in any of the following conversion reactions, in any order, as desired and necessary: One or more can be performed to obtain products of formula (I) or other products of formula (I).

That is,
a) a reaction comprising esterification of an acid functional group,
b) a reaction comprising saponification of an ester functional group to an acid functional group,
c) a reaction comprising the oxidation of an alkylthio group to the corresponding sulfoxide or sulfone,
d) a reaction consisting of conversion of a ketone functional group to an oxime functional group,
e) a reaction consisting of the reduction of a free or esterified carboxyl function to an alcohol function;
f) a reaction consisting of conversion of an alkoxy functional group to a hydroxyl functional group or a hydroxyl functional group to an alkoxy functional group;
g) a reaction comprising the oxidation of an alcohol function to an aldehyde, acid or ketone function,
h) a reaction consisting of conversion of a nitrile group to a tetrazolyl group,
i) a reaction comprising the reduction of a nitrogen-based compound to an amino compound,
j) a reaction consisting of elimination of a protecting group that the protected reactive functional group may have,
k) a reaction consisting of obtaining the corresponding salt by chlorination with an inorganic or organic acid or base,
l) a reaction consisting of resolution into a racemic fraction product,
The product of formula (I) thus obtained can be in either racemic, enantiomeric or diastereomeric isomer form.

  It should also be noted that the reaction of conversion of such substituents to other substituents is performed on the raw material product and the intermediate product as defined above, and then the synthesis by the reaction shown in the above method is continued. it can.

  The product of formula (I) according to the present invention utilizes or adjusts known methods, in particular those described in the literature, such as those described in the work of Larock (RC Larock, Comprehensive Organic Transformations, VCH publishers, 1989). It is thought that it can also be manufactured.

  Thus, to produce a product of formula (I), reactive functional groups such as, for example, hydroxyl, amino, imino, thio or carboxyl groups, are desired in the final product, but the formula (I ) Protection may be necessary when it is not desirable to participate in the reaction to synthesize the product. In particular, conventional protecting groups that are compatible with normal standard practice, such as those described in Green et al. (TW Greene and PGM Wuts, “Protective Groups in Organic Chemistry” John Wiley and Sons, 1991), are used. be able to.

  Various reactive functional groups that a certain compound having the reaction defined above may have can be protected as necessary. These include, for example, free carboxyl, acyl or hydroxyl groups or amino and monoalkylamino groups which can be protected with suitable protecting groups.

  Examples of reactive functional group protection that can be mentioned include, but are not limited to, the following list.

  The hydroxyl group can be protected with an alkyl group such as tert-butyl, trimethylsilyl, tert-butyldimethylsilyl, methoxymethyl, tetrahydropyranyl, benzyl or acetyl.

  The -amino group can be protected with, for example, acetyl (acteyl), trityl, benzyl, tert-butoxycarbonyl, benzyloxycarbonyl or phthalimide groups or other groups known in peptide chemistry.

  Acyl groups such as formyl groups can be protected in the form of cyclic or acyclic acetals or thioacetals such as dimethyl or diethyl acetal or ethylenedioxyacetal or diethylthioacetal or ethylenedithioacetal.

  The acid functionality of the above product is optionally selected from primary or secondary amines, for example in the presence of 1-ethyl-3- (dimethylaminopropyl) carbodiimide hydrochloride at room temperature, for example in methylene chloride. Can be amidated.

  The acid function can be protected in the form of an ester formed with an easily cleavable ester such as, for example, a benzyl ester or tert-butyl ester or an ester known in peptide chemistry.

  These reactions a) to k) can be carried out, for example, according to the method shown below.

a) The above products can be subjected to esterification reactions that can be carried out according to conventional methods known to those skilled in the art at the possible carboxyl functional groups, if desired. .
b) Appropriate conversion of the ester functionality to the acid functionality in the above product is carried out under normal conditions known to the person skilled in the art, if desired, in particular in alcoholic media such as, for example, methanol. It can be carried out by acid or alkaline hydrolysis with sodium hydroxide or potassium hydroxide or hydrochloric acid or sulfuric acid.

  c) Possible alkylthio groups of the above products which may be substituted with one or more halogen atoms, in particular fluorine atoms, which may be substituted with alkyl groups, are known to those skilled in the art, if desired. The corresponding sulfoxides at room temperature, in a solvent such as methylene chloride or dioxane, for example with a peracid such as peracetic acid or meta-chloroperbenzoic acid, or with ozone, oxone or sodium periodate Alternatively, it can be converted to a sulfone functional group. Acquisition of the sulfoxide functional group can be facilitated by an equimolar mixture of a product having an alkylthio group and in particular a reagent such as a peracid.

  Acquisition of the sulfone functional group can be facilitated by a mixture of a product having an alkylthio group and in particular an excess of a reagent such as a peracid.

  d) Reactions consisting of conversion of ketone functional groups to oximes are known to those skilled in the art such as action at room temperature or by heating, for example in the presence of suitably O-substituted hydroxylamines in alcohols such as ethanol. It can be performed under normal conditions.

  e) Possible free or esterified carboxyl functions of the above products can be reduced to alcohol functions by methods known to those skilled in the art, if desired. Possible esterified carboxyl functional groups can be reduced with alcohol functional groups as desired by methods known to those skilled in the art, in particular with lithium aluminum hydride in solvents such as, for example, tetrahydrofuran or dioxane or ethyl ether. can do.

  Possible free carboxyl functional groups of the above products can be reduced to alcohol functional groups, if necessary, in particular with borohydride.

  f) possible alkoxy functional groups of the above products, in particular methoxy functional groups, if necessary with boron tribromide under normal conditions known to the person skilled in the art, for example in a solvent such as methylene chloride. Can be converted to the hydroxyl functionality with pyridine hydrobromide or hydrochloride or with hydrobromic acid or hydrochloric acid under reflux in water or trifluoroacetic acid.

  g) The possible alcohol functionality of the product is optionally obtained by oxidation under normal conditions known to those skilled in the art, for example by obtaining the aldehyde by the action of manganese oxide or by the action of Jones reagent. Can be converted to an aldehyde or acid functional group.

  h) Possible nitrile functional groups of the above products can be prepared, as desired, under normal conditions known to those skilled in the art, for example by Kojima et al. (J. Organometallic Chemistry, 33, 337 (1971) S. Kozima et al.) Can be converted to tetrazolyl functional groups by cycloaddition of metal azides such as sodium azide or trialkyltin azide to nitrile functional groups.

  It should be noted that the reaction in the conversion of carbamate to urea, in particular the conversion of sulfonyl carbamate to sulfonyl urea, can be carried out, for example, in the presence of a suitable amine in the reflux of a solvent such as toluene.

  It will be clear that the above reactions can be carried out as directed or, where appropriate, according to other conventional methods known to those skilled in the art.

  i) Removal of protecting groups, such as those indicated above, under normal conditions known to those skilled in the art, in particular hydrochloric acid, benzenesulfonic acid or para-toluenesulfonic acid, formic acid or trifluoroacetic acid, etc. It can be carried out by acid or base hydrolysis carried out by an acid, by catalytic hydrogenation or with a base such as potassium hydroxide, sodium hydroxide or tetrabutylammonium fluoride.

  The phthalimide group can be eliminated with hydrazine.

  A list of various protecting groups that can be used is found, for example, in patent BF2499995.

  j) If desired, the product can be subjected to a chlorination reaction according to a conventional method known to those skilled in the art, for example, with an inorganic acid or an organic acid or an inorganic base or an organic base.

  k) The possible optically active products described above can be prepared by resolution of the racemic mixture according to the usual methods known to those skilled in the art.

  Possible reactive functional groups can be hydroxyl or amino functional groups. These functional groups are protected using conventional protecting groups. Mention may be made, for example, of the following amino protecting groups: tert-butyl, tert-amyl, trichloroacetyl, chloroacetyl, benzhydryl, trityl, formyl, benzyloxycarbonyl, paratoluenesulfonyl, acetyl, benzenesulfonyl or benzoyl. There is.

  As hydroxyl protecting groups, mention may be made of groups such as formyl, benzyl, acetyl, chloroacetyl, tetrahydropyranyl, trimethylsilyl and tert-butyldimethylsilyl.

  It will be appreciated that those listed above do not limit the invention and that other protecting groups known for example in peptide chemistry can be used. A list of such protecting groups can be found, for example, in French patent BF2499995, the contents of which are incorporated herein by reference.

  The appropriate reaction for removing the protecting group is carried out according to the method shown in the above-mentioned patent BF2499995. A preferred elimination method is acid hydrolysis with an acid selected from hydrochloric acid, benzenesulfonic acid or para-toluenesulfonic acid, formic acid or trifluoroacetic acid. Hydrochloric acid is preferred.

  Hydrolysis reaction of the appropriate group> C = NH to a ketone group is also preferably carried out with an acid such as an aqueous hydrochloric acid solution under reflux.

  The tert-butyldimethylsilyl protecting group can be removed, for example with hydrochloric acid. Appropriate esterification of free OH groups is carried out under conventional conditions. For example, an acid or a functional group derivative in the presence of a base such as pyridine, for example, an anhydride such as acetic anhydride can be used.

  Appropriate esterification or salification of the COOH group is carried out under conventional conditions known to those skilled in the art.

  Appropriate amidation of the COOH group is carried out under conventional conditions. For functional group derivatives of acids, such as symmetrical or hybrid anhydrides, primary or secondary amines can be used.

  The product which is the subject of the present invention has advantageous pharmacological properties. They have been shown in particular to have protein kinase inhibitory properties.

  Among these protein kinases, IGF1R is particularly mentioned.

  The tests in the experimental part below show the inhibitory activity of the products of the invention on such protein kinases. Therefore, these properties make the product of formula (I) of the present invention useful as a medicament in the treatment of malignant tumors.

  The product of formula (I) can also be used in the veterinary field.

  Accordingly, one subject of the present invention is the use of a pharmaceutically acceptable product of formula (I) as a medicament.

  One subject of the present invention is in particular the use of the product of formula (I) as a medicament, the names of which are as follows:

2- {5,6-dimethoxy-1- [2- (4-methylpiperazin-1-yl) ethyl] -1H-indol-3-yl} -1H-pyrrolo [2,3-b] pyridine,
2- (4- {2- [5,6-Dimethoxy-3- (1H-pyrrolo [2,3-b] pyrid-2-yl) -indol-1-yl] ethyl} piperazin-1-yl) ethanol ,
2- (1- {2- [5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] pyrid-2-yl) -indol-1-yl] ethyl} piperid-4-yl) ethanol ,
1 ′-{2- [5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] pyrid-2-yl) indol-1-yl] ethyl}-[1,4 ′] bipiperidyl,
1- {2- [5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] pyrid-2-yl) indol-1-yl] ethyl} piperid-3-ol,
2- {5,6-dimethoxy-1- [2- (4-methylperhydro-1,4-diazepin-1-yl) ethyl] -1H-indol-3-yl] -1H-pyrrolo [2,3 -B] pyridine,
2- [5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] pyrid-2-yl) indol-1-yl] -1- (4-hydroxypiperidin-1-yl) ethanone,
2- [5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] pyrid-2-yl) indol-1-yl] -1-thiazolidin-3-ylethanone,
4-{[5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] pyrid-2-yl) indol-1-yl] acetyl} -1-methylpiperazin-2-one,
4-chloro-2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyridine,
2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyridine-4-carbonitrile,
4-chloro-2- [5,6-dimethoxy-1- (2-morpholin-4-ylethyl) -1H-indol-3-yl] -1H-pyrrolo [2,3-b] pyridine,
2- (1- {2- [3- (4-Chloro-1H-pyrrolo [2,3-b] pyrid-2-yl) -5,6-dimethoxyindol-1-yl] ethyl} piperidi-4- Yl) ethanol,
4-Chloro-2- {5,6-dimethoxy-1- [2- (4-methylpiperazin-1-yl) ethyl] -1H-indol-3-yl} -1H-pyrrolo [2,3-b] Pyridine,
2- {5,6-dimethoxy-1- [2- (4-methylpiperazin-1-yl) ethyl] -1H-indol-3-yl} -1H-pyrrolo [2,3-b] pyridine-4- Carbonitrile,
2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -5-fluoro-1H-pyrrolo [2,3-b] pyridine,
2- [5,6-dimethoxy-1- (2-morpholin-4-ylethyl) -1H-indol-3-yl] -5-fluoro-1H-pyrrolo [2,3-b] pyridine,
2- {5,6-dimethoxy-1- [2- (4-methylpiperazin-1-yl) ethyl] -1H-indol-3-yl} -5-fluoro-1H-pyrrolo [2,3-b] Pyridine,
2- [5-methoxy-1-methyl-3- (1H-pyrrolo [2,3-b] pyrid-2-yl) -1H-indol-6-yloxy] -1-morpholin-4-ylethanone,
2- [5-Methoxy-1-methyl-3- (1H-pyrrolo [2,3-b] pyrid-2-yl) -1H-indol-6-yloxy] -1- (4-methyl [1,4 ] Diazepan-1-yl) ethanone,
2- [5-Methoxy-1-methyl-3- (1H-pyrrolo [2,3-b] pyrid-2-yl) -1H-indol-6-yloxy] -N- [4- (4-methylpiperazine -1-yl) phenyl] aceto-amide,
2- [5-Methoxy-1-methyl-3- (1H-pyrrolo [2,3-b] pyrid-2-yl) -1H-indol-6-yloxy] -1- (4-methylpiperazine-1- Il) Ethanon,
1- {4- [2- (2-hydroxyethoxy) ethyl] piperazin-1-yl} -2- [5methoxy-1-methyl-3- (1H-pyrrolo [2,3-b] pyrid-2- Yl) -1H-indole-6-yloxy] ethanone,
(3aS, 6aS) -5- {2- [5-Methoxy-1-methyl-3- (1H-pyrrolo [2,3-b] pyrid-2-yl) -1H-indol-6-yloxy] acetyl} Hexahydropyrrolo- [3,4-c] pyrrol-1-one trifluoroacetate,
2- {5-Methoxy-1-methyl-6- [3- (4-methylperhydro-1,4-diazepin-1-yl) propoxy] -1H-indol-3-yl} -1H-pyrrolo [2 , 3-b] pyridine,
4-Chloro-2- {1-methyl-5-methoxy-6- [2- (4-methylpiperazin-1-yl) ethoxy] -1H-indol-3-yl} -1H-pyrrolo [2,3- b] pyridine,
4-chloro-2- {1-methyl-5-methoxy-6- [2- (4-piperidylpiperid-1-yl) ethoxy] -1H-indol-3-yl} -1H-pyrrolo [2,3 -B] pyridine,
4-Chloro-2- {5-methoxy-1-methyl-6- [2- (2-pyrrolidineethyl-amino) ethoxy] -1H-indol-3-yl} -1H-pyrrolo [2,3-b] Pyridine,
4-chloro-2- {1-methyl-5-methoxy-6- [2- (2-piperidineethyl-amino) ethoxy] -1H-indol-3-yl} -1H-pyrrolo [2,3-b] Pyridine,
And the prodrugs thereof, wherein the product of formula (I) is racemic, enantiomeric or diastereomeric isomer form, and of the product of formula (I) with or without inorganic base and organic It may be a pharmaceutically acceptable addition salt with a base.

  One subject of the present invention is in particular the use of the product of formula (I) as a medicament, the names of which are as follows:

2- {5,6-dimethoxy-1- [2- (4-methylpiperazin-1-yl) ethyl] -1H-indol-3-yl} -1H-pyrrolo [2,3-b] pyridine,
2- (4- {2- [5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] pyridin-2-yl) indol-1-yl] ethyl] piperazin-1-yl) ethanol,
2- (1- {2- [5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] pyridin-2-yl) indol-1-yl] ethyl} piperidin-4-yl) ethanol,
1 ′-(2- [5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] pyridin-2-yl) indol-1-yl] ethyl}-[1,4 ′] bipiperidinyl,
1- (2- [5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] pyridin-2-yl) -indol-1-yl] ethyl} piperidin-3-ol,
2- {5,6-dimethoxy-1- [2- (4-methylperhydro-1,4-diazepin-1-yl) ethyl] -1H-indol-3-yl} -1H-pyrrolo [2,3 -B] pyridine,
2- [5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] pyridin-2-yl) indol-1-yl] -1- (4-hydroxypiperidin-1-yl) ethanone,
2- [5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] pyridin-2-yl) indol-1-yl] -1-thiazolidin-3-ylethanone,
4-{[5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] pyridin-2-yl) indol-1-yl] acetyl} -1-methylpiperazin-2-one,
4-chloro-2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyridine,
2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyridine-4-carbonitrile,
4-chloro-2- [5,6-dimethoxy-1- (2-morpholin-4-ylethyl) -1Hindol-3-yl] -1H-pyrrolo [2,3-b] pyridine,
2- (1- {2- [3- (4-Chloro-1H-pyrrolo [2,3-b] pyridin-2-yl) -5,6-dimethoxyindol-1-yl] ethyl} piperidine-4- Yl) ethanol,
4-Chloro-2- {5,6-dimethoxy-1- [2- (4-methylpiperazin-1-yl) ethyl] -1H-indol-3-yl} -1H-pyrrolo [2,3-b] Pyridine,
2- {5,6-dimethoxy-1- [2- (4-methylpiperazin-1-yl) ethyl] -1H-indol-3-yl} -1H-pyrrolo [2,3-b] pyridine-4- Carbonitrile,
2- {5,6-dimethoxy-1-methyl-1H-indol-3-yl) -5-fluoro-1H-pyrrolo [2,3-b] pyridine,
2- [5,6-dimethoxy-1- [2-morpholin-4-ylethyl) -1H-indol-3-yl] -5-fluoro-1H-pyrrolo [2,3-b] pyridine,
2- {5,6-dimethoxy-1- [2- (4-methylpiperazin-1-yl) ethyl] -1H-indol-3-yl} -5-fluoro-1H-pyrrolo [2,3-b] Pyridine,
2- [5-methoxy-1-methyl-3- (1H-pyrrolo [2,3-b] pyridin-2-yl) -1H-indol-6-yloxy] -1-morpholin-4-ylethanone,
2- [5-Methoxy-1-methyl-3- (1H-pyrrolo [2,3-b] pyridin-2-yl) -1H-indol-6-yloxy] -1- (4-methyl- [1, 4] diazepan-1-yl) ethanone,
2- [5-Methoxy-1-methyl-3- (1H-pyrrolo [2,3-b] pyridin-2-yl) -1H-indol-6-yloxy] -N- [4- (4-methylpiperazine) -1-yl) phenyl] acetamide,
2- [5-Methoxy-1-methyl-3- (1H-pyrrolo [2,3-b] pyridin-2-yl) -1H-indol-6-yloxy] -1- (4-methylpiperazine-1- Il) Ethanon,
1- {4- [2- (2-hydroxyethoxy) ethyl] piperazin-1-yl} -2- [5-methoxy-1-methyl-3- (1H-pyrrolo [2,3-b] pyridine-2 -Yl) -1H-indol-6-yloxy] ethanone,
(3aS, 6aS) -5- {2- [5-Methoxy-1-methyl-3- (1H-pyrrolo- [2,3-b] pyridin-2-yl) -1H-indol-6-yloxy] acetyl } Hexahydro-pyrrolo [3,4-c] pyrrol-1-one trifluoroacetate,
2- {5-Methoxy-1-methyl-6- [3- (4-methylperhydro-1,4-diazepin-1-yl) propoxy] -1H-indol-3-yl} -1H-pyrrolo- [ 2,3-b] pyridine,
4-chloro-2- {1-methyl-5-methoxy-6- [2- (4-methylpiperazin-1-yl) ethoxy-1H-indol-3-yl} -1H-pyrrolo [2,3-b ] Pyridine,
4-chloro-2- {1-methyl-5-methoxy-6- [2- (4-piperidyl-piperidin-1-yl) ethoxy-1H-indol-3-yl} -1H-pyrrolo [2,3- b] -pyridine,
4-Chloro-2- {5-methoxy-1-methyl-6- [2- (2-pyrrolidineethyl-amino) ethoxy] -1H-indol-3-yl} -1H-pyrrolo [2,3-b] Pyridine,
4-chloro-2- {1-methyl-5-methoxy-6- [2- (2-piperidineethylamino) ethoxy-1H-indol-3-yl} -1H-pyrrolo [2,3-b] pyridine,
And the prodrugs thereof, wherein the product of formula (I) is racemic, enantiomeric or diastereomeric isomer form, and of the product of formula (I) with or without inorganic base and organic It may be a pharmaceutically acceptable addition salt with a base.

  The product can be administered parenterally, orally, lingually, rectally or topically.

  One subject of the present invention is also a pharmaceutical composition comprising as active ingredient at least one pharmaceutical of formula (I).

  These compositions can be provided in the form of solutions or suspensions for injection, tablets, coated tablets, capsules, syrups, suppositories, creams, ointments and lotions. These pharmaceutical forms are manufactured according to the usual methods. The active ingredients are aqueous or non-aqueous media, talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, animal or vegetable fatty substances, paraffin derivatives, glycols, various wetting agents, dispersants or emulsifiers. Can be incorporated into excipients commonly used in these compositions, such as preservatives.

  Usual doses that may vary depending on the individual being treated and the condition being studied can be, for example, 10 mg to 500 mg / day in humans when administered orally.

  Accordingly, the present invention provides a pharmaceutical preparation of a protein of the formula (I) as defined above or a product of the formula (I) as defined above in the manufacture of a medicament for inhibiting the activity of protein kinases, particularly protein kinases. It relates to the use of acceptable salts.

  The invention therefore relates to the use of a product of formula (I) as defined above or a pharmaceutically acceptable salt of the product of formula (I), wherein said protein kinase is a tyrosine protein kinase.

  Therefore, in the present invention, the protein kinase is IGF1, Raf, EGF, PDGF, VEGF, Tie2, KDR, Flt1-3, FAK, Src, Abl, cKit, cdk1-9, Aurora1-2, cdc7, Akt, Pdk, S6K, Jnk, IR, FLK-1, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, PLK and a product of formula (I) as defined above or a product of formula (I) selected from the group of The use of pharmaceutically acceptable salts.

  Accordingly, the present invention provides the production of formula (I) as defined above, wherein said protein kinase is more particularly selected from the group of IGF1, cdc7, Aurora1-2, Src, Jnk, FAK, KDR, IR and Tie2. Or the use of a pharmaceutically acceptable salt of the product of formula (I).

  The present invention therefore relates to the use of a product of formula (I) as defined above or a pharmaceutically acceptable salt of a product of formula (I) as defined above, wherein said protein kinase is IGF1R.

  The present invention further provides the use of a product of formula (I) as defined above or a pharmaceutically acceptable salt of a product of said formula (I) as defined above, wherein said protein kinase is in cell culture, and mammals It relates to its use in animals.

  Accordingly, the present invention relates to formula (I) as defined above for the manufacture of a medicament for the prevention or treatment of diseases characterized by impaired protein kinase activity, in particular such diseases in mammals. Or the use of a pharmaceutically acceptable salt of the product of formula (I).

  The present invention relates to vascular proliferative disorder, fibrotic disorder, mesangial cell proliferative disorder, metabolic disorder, allergy, asthma, thrombosis, nervous system disease, retinopathy, psoriasis, rheumatoid arthritis, diabetes, muscle degeneration, neoplastic disease and cancer. Use of a product of formula (I) as defined above or a pharmaceutically acceptable salt of a product of formula (I) as defined above in the manufacture of a medicament for the prevention or treatment of a disease belonging to the group It is.

  The present invention therefore provides the use of a product of formula (I) as defined above or a pharmaceutically acceptable salt of a product of formula (I) as defined above in the manufacture of a medicament for the treatment of neoplastic diseases. It is about.

  The invention relates in particular to the use of a product of formula (I) as defined above or a pharmaceutically acceptable salt of a product of said formula (I) in the manufacture of a medicament for the treatment of cancer. It is.

  Of these cancers, the present invention is most particularly focused on the treatment of solid tumors as well as cancers that are resistant to cytotoxic drugs.

  Among these cancers, the present invention is most particularly disclosed in the following: breast cancer, stomach cancer, colon cancer, lung cancer, ovarian cancer, uterine cancer, brain tumor, kidney cancer, laryngeal cancer, lymphoid cancer, thyroid cancer, genitourinary cancer, bladder And the treatment of cancer of the ducts including prostate, osteosarcoma, pancreatic cancer and melanoma.

  The present invention more particularly focuses on the treatment of breast cancer, colon cancer and lung cancer.

  The invention therefore relates to the use of a product of formula (I) as defined above or a pharmaceutically acceptable salt of a product of formula (I) as defined above in the manufacture of a medicament for cancer chemotherapy. It is.

  As a medicament according to the invention for cancer chemotherapy, the product of formula (I) according to the invention can be used alone or in combination with chemotherapy or radiation therapy or in combination with other therapeutic agents.

  The invention therefore relates in particular to a pharmaceutical composition as defined above, which contains in addition to the active ingredient other pharmaceuticals for chemotherapy against cancer.

  Such therapeutic agents can be commonly used anti-tumor agents.

  Examples of known protein kinase inhibitors include butyrolactone, flavopiridol, 2- (2-hydroxyethylamino) -6-benzylamino-9-methylpurine, olomucine, Gleevec and Iressa, among others. be able to.

  Therefore, the product of formula (I) according to the present invention can also be used advantageously in combination with an antiproliferative agent. Examples of such antiproliferative agents include aromatase inhibitors, antiestrogens, topoisomerase I inhibitors, topoisomerase II inhibitors, agents active against microtubules, alkylating agents, histone deacetylase inhibitors, farnesyl Transferase inhibitors, COX-2 inhibitors, MMP inhibitors, mTOR inhibitors, antineoplastic antimetabolites, platinum compounds, compounds that reduce protein kinase activity and antiangiogenic compounds, gonadorelin agonists, antiandrogens, There are bengamides, bisphosphonates and trastuzumab, but are not limited to those listed here.

  Therefore, examples that may be mentioned include anti-microtubule drugs such as taxoids, vinca alkaloids, alkylating agents (such as cyclophosphamide), DNA intercalating agents such as cisplatin, and topoisomerases such as camptothecin and derivatives. There are interacting drugs, anthracyclines such as adriamycin, antimetabolites such as 5-fluorouracil and derivatives.

  The present invention therefore relates to a product of formula (I) as a protein kinase inhibitor, said product of formula (I) comprising a racemic, enantiomeric or diastereomeric isomer form, as well as of said formula (I) It may also be a pharmaceutically acceptable addition salt of the product with inorganic and organic acids or with inorganic and organic bases and their prodrugs.

  The invention particularly relates to the product of formula (I) as defined above as an IGF1R inhibitor.

  The raw materials for synthesizing the products of formula (I) according to the invention are known, described in the documents of the person skilled in the art, or may be commercially available, It can be produced according to a known ordinary method or according to the method described in the attached scheme.

  The experimental part below provides, in more detail, an explanation of the synthesis described in the scheme of the present invention, and the preparation of Examples 1-175 of the present application. The examples described below for manufacture illustrate the invention regardless of whether it is involved in the manufacture of a product or in the manufacture of a pharmaceutical composition. It is not limited.

  The analytical and purification methods used to characterize the product in the following preparation are as follows.

Mass spectrometry:
The spectrum was obtained by electron impact (EI) and / or chemical desorption-ionization (CI) (reactant gas: ammonia) on a Finnigan SSQ7000 spectrometer.

Analytical method: Method A
Unless otherwise clearly indicated, reverse phase liquid chromatography mass spectral (LC / MS) analysis was performed on a Micromass LCT type instrument connected to an HP1100 instrument. Product abundance was measured by a HPG1315A diode array detector and a Sedex 65 light scattering detector over a wavelength of 200-600 nm (DAD). Acquisition of the mass spectrum was performed over a range of 180-800. Data analysis was performed using MicroLus Mass Software (MassLynx) software. Separation is carried out on a Hypersil BDSC 18, 3 μm (50 × 4.6 mm) column, containing 0.05% (volume ratio) trifluoroacetic acid (TFA) over 3.5 minutes at a flow rate of 1 cm ³ / min. Elution was performed with a linear gradient of water containing 5-90% acetonitrile / 0.05% (volume ratio) TFA. The total analysis time including the column re-equilibration period is 7 minutes.

Purification method: Method B
In general, the resulting compounds consist of a Waters 600 gradient pump, a Waters 515 regeneration pump, a Waters ReagentManager dilution pump, a Waters 2700 autoinjector, two Rheodyne LabPros. Phase Liquid Chromatography Mass Spectrometry (LC /) using a Waters FractionLynx system consisting of a type valve, a Waters 996 diode array detector, a Waters ZMD type mass spectrometer and a Gilson 204 type fraction collector MS). The system was controlled by Waters Fraction Links software. The separation was performed alternately on two Waters Symmetry columns (C18, 5 μm, 19 × 50 mm, catalog reference number 186021010), one column containing 0.07% (volume ratio) trifluoroacetic acid 95 While regenerating with a / 5 (volume ratio) water / acetonitrile mixture, separation was performed using the other column. The columns were eluted using a linear gradient of 0.07% (volume ratio) trifluoroacetic acid-containing acetonitrile / 0.07% (volume ratio) trifluoroacetic acid-containing water at a flow rate of 10 cm ³ / min. At the outlet of the separation column, 1/1000 of the effluent is separated using an LC Packing Accurate device, diluted with methanol at a flow rate of 0.05 cm ³ / min, sent to the detector, and diode array detection 75% was sent to the vessel and the remaining 25% was sent to the mass spectrometer. The remaining portion of the effluent (999/1000) was sent to the fraction collector where the effluent was discarded unless the expected product mass was detected by the fraction lynx software. The molecular formula of the expected product is sent to Fraction Links software, which initiates product recovery if the detected mass signal corresponds to [M + H] ⁺ and / or [M + Na] ⁺ ions. In some cases, if strong ions corresponding to [M + 2H] ⁺⁺ are detected according to the analytical LC / MS results, a value corresponding to half the calculated molecular weight (MW / 2) is also sent to the Fraction Links software. Under these conditions, recovery is also initiated when mass signals of [M + 2H] ⁺⁺ and / or [M + Na + H] ⁺⁺ ions are detected. The product was collected in a tared glass test tube.

Solutions with a volume greater than 0.5 cm ³ are purified in two stages, otherwise in one stage. Fractions are collected in the lysate before labeling and before taring, and only test tubes containing compounds of the expected molecular weight are used.

  Unless otherwise clearly indicated, the component elution gradients used in these purifications are as follows:

  In the present specification, the method referred to as “Method D” uses the same apparatus as described above, but the elution gradient is as follows.

  In the present specification, the method referred to as “Method E” uses the same apparatus as described above, but the elution gradient is as follows.

  In this specification, the method referred to as “Method F” uses the same apparatus as described above, but the elution gradient is as follows.

  In this specification, the method referred to as “Method G” uses the same apparatus as described above, but the elution gradient is as follows.

Example 1
2- (5,6-dimethoxy-1-vinyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyridine trifluoroacetate 2- (5,6-dimethoxy-1-vinyl -1H-Indol-3-yl) -1H-pyrrolo- [2,3-b] pyridine trifluoroacetate can be prepared by the following method.

Dimethyl of 2- (5,6-dimethoxy-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine (0.5 g; 1.117 mmol) The formamide (5 mL) solution is placed in a 10 mL round bottom flask sealed with a septum and 1-bromo-2-chloroethane is added (0.865 g; 0.5 mL; 6.032 mmol). The reaction mixture is stirred at room temperature and sodium hydride (0.1 g; 3.35 mmol) is added in 33 successive portions. When the reaction mixture turns green, 1-bromo-2-chloroethane (0.865 g; 0.5 cm ³ ; 6.03 mmol) is added. The reaction is monitored by TLC (50/50 cyclohexane / ethyl acetate) until the feed disappears. The reaction mixture is placed in a mixture of 20 mL water and saturated ammonium chloride solution (20 mL). Ethyl acetate (50 mL) is added, followed by separation by settling and extraction with ethyl acetate (30 mL). The combined extracts are washed with saturated ammonium chloride solution (30 mL), dehydrated with magnesium sulfate, and evaporated under reduced pressure. The solvent evaporation product is taken up in a 50/50 cyclohexane / ethyl acetate mixture and left at room temperature for 24 hours. The resulting solid is filtered off, washed with a 72/25 cyclohexane / ethyl acetate mixture (15 mL) and dried in vacuo. The resulting compound is purified by LCMS (Method B). 2- [1- (2-Chloroethyl) -5,6-dimethoxy-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine (0. 33 g) is isolated, its properties are as follows:

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SOd 6, δ ppm value): 2.30 (s: 3H); 3.73 (s: 3H); 3.90 (s: 3H); 4.09 (t , J = 6 Hz: 2H); 4.63 (t, J = 6 Hz: 2H); 6.76 (s: 1H); 6.95 (s: 1H); 7.26 (d, J = 8.5 Hz) 7.2 (s: 1H); 7.32 (dd, J = 8 and 5 Hz: 1H); 7.55 (s: 1H); 7.58 (d, J = 8.5 Hz: 2H) ); 7.96 (dd, J = 8 and 1.5 Hz: 1H); 8.38 (dd, J = 5 and 1.5 Hz: 1H).

Mass spectrum: (EI): m / z = 509 [M] ⁺ ; m / z = 354 [M−C ₇ H ₇ NSO ₂ ] ⁺ (reference peak).

  2- (5,6-Dimethoxy-1-vinyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyridine trifluoroacetate (0.042 g) isolated and its properties Is as follows.

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SOd 6, δ ppm value): 3.89 (s: 3H); 3.93 (s: 3H); 4.86 (wide d, J = 8.5 Hz: 1H) ); 5.32 (wide d, J = 15.5 Hz: 1H); 6.97 (d, J = 2 Hz: 1H); 7.11 (dd, J = 8 and 5 Hz: 1H); 7.46 ( s: 1H): 7.47 (s: 1H); 7.63 (dd, J = 15.5 and 8.5 Hz: 1H); 7.99 (wide d, J = 8 Hz: 1H); 8.21 (Dd, J = 5 and 1.5 Hz: 1H); 8.34 (s: 1H); 11.96 (undivided peak: 1H).
Mass spectrum: (EI): m / z = 319 [M] ⁺ (reference peak).

  2- (5,6-dimethoxy-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine is prepared according to the method described in patent WO03 / 0006881A1. can get.

(Examples 2-79)
A) Preparation: 2- [1- (2-Iodoethyl) -5,6-dimethoxy-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] -Pyridine can be produced by the following method.

  2- [1- (2-Chloroethyl) -5,6-dimethoxy-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3- described in Example 1 b] -Pyridine (0.331 g; 649 μmol) and sodium iodide (0.195 g; 1.298 mmol) in methyl ethyl ketone (5 mL) are placed in a 10 mL round bottom flask. The reaction mixture is refluxed for 16 hours. After evaporation, the product is taken up in a mixture of water (15 mL) and ethyl acetate (15 mL). After separation by settling and extraction with ethyl acetate (2 × 15 mL), the organic extracts are combined, dried over magnesium sulfate and evaporated under reduced pressure. The solvent residue is chromatographed on silica gel, elution being carried out with a mixture of cyclohexane and ethyl acetate (50/50). Fractions containing the expected compound were combined and evaporated to give 2- [1- (2-iodoethyl) -5,6-dimethoxy-1H-indol-3-yl] -1- (toluene-4-sulfonyl). -1H-pyrrolo [2,3-b] pyridine (0.24 g; 69%) was obtained, the properties of which are as follows:

LC / MS analysis: tr = 3.9 min, m / z = 601.99 [M + H] ⁺ .

b) Alkylation of Examples 2 to 79 A dimethylformamide solution of the following amine at a concentration of 90 μmol / dimethylformamide 0.5 mL is placed in a tared and labeled glass tube (1.2 × 10 cm). Compound 2- [1- (2-iodoethyl) -5,6-dimethoxy-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo (2,3-b) pyridine Dissolve in dimethylformamide at a concentration of 30 μmol / 0.5 mL of solvent.

  0.5 mL of each solution prepared above was added to 0.5 mL / well of the above 2- [1- (2-iodoethyl) -5,6-dimethoxy-1H-indol-3-yl] -1- (toluene- Partition with 4-dimethyl) -1H-pyrrolo [2,3-b] pyridine in dimethylformamide in a suitable reactor for parallel synthesis and add 0.01-0.015 g of potassium carbonate. The reactor is sealed with a septum and then placed at 80 ° C. for 16 hours with shaking on orbit. After returning to room temperature, the reactor contents are filtered and purified by reverse-phase liquid chromatography mass spectrometry (Method B). After analyzing the fractions for solvent evaporation, weighing and preparative reverse phase liquid chromatography mass spectrometry results, the intermediate compound is isolated and identified and used in the next step.

c) Detosylation of Examples 2 to 79 Each compound isolated above was dissolved in 0.1 g / mL methanolic potassium hydroxide solution (0.5 mL), and a stopper was attached to each tube at room temperature. Shake for 60 hours. The contents of each tube are evaporated under reduced pressure, diluted with distilled water (1.5 mL) and extracted with methylene chloride (3 × 0.9 mL). The organic extracts are combined, dehydrated with magnesium sulfate, filtered into a tared and labeled glass tube (1.2 × 10 cm) and evaporated. The compound isolated after evaporation of the solvent is weighed, diluted with dimethyl sulfoxide (0.5 mL) and purified by reverse phase liquid chromatography mass spectrometry in preparative mode (Method B). The fraction containing the expected molar mass of the compound is evaporated, weighed and diluted with dimethyl sulfoxide to 10 mM. The expected compound is identified and characterized by reverse phase liquid chromatography mass spectrometry (Method A). The results obtained are shown in the table below.

(Example 80)
{2- [5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] -pyridin-2-yl) indol-1-yl] ethyl}-(2-methoxyethyl) methyl-amine tri Fluoroacetate a) {2- [5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] pyridin-2-yl) indol-1-yl] ethyl)-(2-methoxyethyl) methyl Amine trifluoroacetate can be produced by the following method.

  (2- {5,6-dimethoxy-3- (1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridin-2-yl) indol-1-yl] ethyl)-(2 -Methoxy-ethyl) methylamine trifluoroacetate salt (0.0152 g; 22.46 μmol) was dissolved in methanolic potassium hydroxide solution (0.5 mL; potassium hydroxide 0.1 g / methanol 1 mL) and at room temperature for 48 hours. Stir. After evaporation of the solvent, the residue is taken up in 0.7 mL of dimethyl sulfoxide and 12N aqueous hydrochloric acid (50/50 volume ratio) with stirring. After returning to room temperature, dimethyl sulfoxide (0.35 mL) is added and purification is performed by reverse phase liquid chromatography mass spectrometry (Method B). Fractions containing the expected compound are combined and evaporated.

  {2- [5,6-Dimethoxy-3- (1H-pyrrolo [2,3-b] pyridin-2-yl) indol-1-yl] ethyl}-(2-methoxyethyl) methylamine trifluoroacetic acid A salt (0.0094 g; 80%) was isolated and its properties are as follows.

LC / MS analysis: tr = 2.4 min, m / z = 409.24 [M + H] ⁺ .

  b) (2- {5,6-dimethoxy-3- [1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridin-2-yl) indol-1-yl} ethyl)- (2-Methoxy-ethyl) methylamine trifluoroacetate can be produced by the following method.

  {2- [1- (2-Chloroethyl) -5,6-dimethoxy-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] -pyridine ( 0.021 g; 50 μmol) of N-methylpyrrolidine (0.5 mL) was placed in a 5 mL conical bottom Wheaton reactor and 2-methoxy-N-methylamine (0.013 g; 150 μmol) and potassium carbonate (0.021 g). 150 μmol) is added. The reaction mixture is stirred and heated at 70 ° C. overnight. After returning to room temperature, the mixture is filtered, evaporated to dryness, the residue is taken up in dimethyl sulfoxide and purified by reverse phase liquid chromatography mass spectrometry (Method B). After fractionation and solvent evaporation, (2- {5,6-dimethoxy-3- [1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridin-2-yl) indole -1-yl} ethyl)-(2-methoxyethyl) methylamine trifluoroacetate (0.015 g; 45%) was isolated and its properties are as follows.

LC / MS analysis (Method B): tr = 5.6 min, m / z = 563.35 [M + H] ⁺ .

(Example 81)
2-[(3- {2- [5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] -pyridin-2-yl) indol-1-yl] ethylamino} propyl) (2- Hydroxyethyl) amino] ethanol trifluoroacetate a) 2-[(3- {2- [5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] pyridin-2-yl) indole- 1-yl] ethylamino} propyl) (2-hydroxyethyl) -amino] ethanol trifluoroacetate can be prepared by the following method.

  (2-[[3- (2- {5,6-dimethoxy-3- (1- [toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridin-2-yl] indole-1- Yl} ethylamino) -propyl] (2-hydroxyethyl) amino] ethanol trifluoroacetate (0.013 g; 17.6 μmol) in methanolic potassium hydroxide solution (0.5 mL; potassium hydroxide 0.1 g / The mixture is dissolved in methanol (1 mL) and stirred at room temperature for 48 hours, and after the solvent has been distilled off, the residue is taken up in 0.7 mL of a mixture of dimethyl sulfoxide and 12N aqueous hydrochloric acid (50/50 volume ratio). Thereafter, 0.35 mL of dimethyl sulfoxide is added and purification is performed by reverse phase liquid chromatography mass spectrometry (Method B). The solvent was distilled off to give 2-[(3- {2- [5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] pyridin-2-yl) indol-1-yl] ethylamino]. Propyl) (2-hydroxyethyl) amino] ethanol trifluoroacetate (0.005 g; 39%) is obtained, the properties of which are as follows:

LC / MS analysis: tr = 3.1 min, m / z = 482.02 [M + H] ⁺ .

  b) 2-[[3- {5,6-dimethoxy-3- [1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridin-2-yl] indol-1-yl} Ethylamino) propyl]-(2-hydroxyethyl) amino] ethanol trifluoroacetate can be prepared by the following method.

  2- [1- (2-Chloroethyl) -5,6-dimethoxy-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] -pyridine (0 .02 g; 50 μmol) of N-methylpyrrolidone (0.5 mL) in a 5 mL conical bottom Wheaton reactor, and N- (3-aminopropyl) diethanolamine (0.024 g; 150 μmol) and potassium carbonate (0.021 g) 150 μmol) is added. The reaction mixture is stirred and heated at 70 ° C. overnight. After returning to room temperature, the mixture is filtered, evaporated to dryness, the residue is taken up in dimethyl sulfoxide and purified by reverse phase liquid chromatography mass spectrometry (Method B). After fractionation and evaporation, 2-[[3- (2- {5,6-dimethoxy-3- [1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine) -2-yl] -indol-1-yl} ethylamino) propyl]-(2hydroxyethyl) amino] ethanol trifluoroacetate salt (0.013 g, 35%) and its properties are as follows: It is.

LC / MS analysis (Method B): tr = 5 min, m / z = 636.43 [M + H] ⁺ .

(Example 82)
2- (4- {3- [5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] pyridin-2-yl) indol-1-yl] propyl} piperazin-1-yl) ethanol Trifluoroacetate a) 2- (4- {3- [5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] pyridin-2-yl) indol-1-yl] propyl} piperazine- 1-yl) ethanol trifluoroacetate can be prepared by the following method.

  2- [4- (3- {5,6-dimethoxy-3- [1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridin-2-yl] indol-1-yl] (Propyl) piperazin-1-yl] ethanol trifluoroacetate (0.038 g; 52.2 μmol) in methanolic potassium hydroxide solution (3 mL, potassium hydroxide 0.1 g / methanol 1 mL) 3 × 10 cm) and stirred at 20 ° C. for 72 hours. The solid is filtered off and purified by reverse phase liquid chromatography mass spectrometry (Method E). Fractions containing the expected compound were combined and evaporated under reduced pressure to give 2- (4- {3- [5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] pyridine-2- Yl) indol-1-yl] propyl} piperazin-1-yl) ethanol trifluoroacetate (0.022 g; 90%) is obtained, the properties of which are as follows:

LC / MS analysis: tr = 2.7 min, m / z = 464.29 [M + H] ⁺ .

  b) 2- [4- (3- {5,6-dimethoxy-3- [1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridin-2-yl] indole-1- Yl} propyl) piperazin-1-yl] ethanol trifluoroacetate can be prepared by the following method.

  2- [1- (3-Iodopropyl) -5,6-dimethoxy-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine (0 0.04 g; 65 μmol) in dimethylformamide (0.5 mL) was placed in a lysis vessel (1.3 × 10 cm), and potassium carbonate (0.027 g; 195 μmol) and N- (2-hydroxyethyl) piperazine (0.025 g) 195 μmol) is added in that order. The reactor is stirred at 60 ° C. for 16 hours. After returning to 21 ° C. and filtration, the resulting solution is purified by reverse phase liquid chromatography mass spectrometry (Method B). Fractions containing the expected compound were combined and evaporated under reduced pressure to give 2- [4- (3- {5,6-dimethoxy-3- [1- (toluene-4-sulfonyl) -1H-pyrrolo [ 2,3-b] pyridin-2-yl] indol-1-yl} propyl) piperazin-1-yl] ethanol trifluoroacetate (0.038 g, 69%) was obtained, which was Use.

  c) 2- [1- (3-Iodopropyl) -5,6-dimethoxy-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine Can be manufactured by the following method.

2- [1- (3-Chloropropyl) -5,6-dimethoxy-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine (0 395 g; 753.8 μmol) and sodium iodide (0.169 g; 1.13 mmol) in methyl ethyl ketone (10 mL) are placed in a 50 mL 1-neck flask and refluxed. After 16 hours, sodium iodide (0.169 g; 1.13 mmol) is added and reflux is maintained for an additional 5 hours. The reaction mixture is evaporated under reduced pressure and the residue is dissolved in 50 mL of ethyl acetate, transferred to a separatory funnel and washed twice with 30 mL of distilled water. The organic extract was dried over magnesium sulfate, filtered and evaporated under reduced pressure to give the crude compound, which was purified by chromatography on silica gel (10 g, silica 20-40 μm), elution being cyclohexane And a mixture of ethyl acetate (70/30; volume ratio) at 10 mL / min. Fractions containing the expected compound were combined and evaporated to give 2- [1- (3-iodopropyl) -5,6-dimethoxy-1H-indol-3-yl] -1- (toluene-4-sulfonyl) ) -1H-pyrrolo [2,3-b] pyridine was obtained in the form of an amorphous solid (0.287 g, 62%), the properties of which are as follows: Mass spectrum (EI): m / z = 615 [M] ⁺ ; m / z = 460 [M−C ₇ H ₇ NSO ₂ ] ⁺ ;

m / z = 333 [460-I] ⁺ (reference peak).

  d) 2- [1- (3-Chloropropyl) -5,6-dimethoxy-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine Can be manufactured by the following method.

  2- (5,6-dimethoxy-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] (0.447 g; 998 μmol) of dimethylformamide (10 mL ) Place the solution in a 25 mL 3-neck flask maintained under argon and add sodium hydride (0.0898 g; 2.99 mmol). The mixture is stirred at 21 ° C. for 10 minutes and 1-bromo-3-chloropropane (0.514 g; 2.99 mmol) is added. The reaction is carried out at this temperature for 1 hour 30 minutes. The reaction mixture is taken up in 100 mL water and extracted three times with 50 mL ethyl acetate. The organic extracts are combined, washed with 50 mL of saturated ammonium chloride solution, dried over magnesium sulfate, and evaporated. The oil is isolated and it is triturated in diisopropyl ether. The product solid is filtered off. 2- [1- (3-Chloropropyl) -5,6dimethoxy-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine as a white solid In the form (0.395 g; 75.5%) and its properties are as follows:

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SOd 6, δ ppm value) 2.30 (s: 3H); 2.31 (mt: 2H); 3.66 (t, J = 6.5 Hz: 2H); 3.74 (s: 3H); 3.90 (s: 3H); 4.41 (wide t, J = 6.5 Hz: 2H); 6.79 (s: 1H); 6.96 (s: 1H) 7.21 (s: 1H); 7.26 (wide d, J = 8.5 Hz: 2H); 7.32 (dd, J = 8 and 5 Hz: 1H); 7.51 (s: 1H) 7.58 (d, J = 8.5 Hz: 2H); 7.96 (dd, J = 8 and 1.5 Hz: 1H); 8.37 (dd, J = 5 and 1.5 Hz: 1H).

Mass spectrum (EI): m / z = 523 [M] ⁺ ; m / z = 368 [M−C ₇ H ₇ NSO ₂ ] ⁺ (reference peak).

  2- (5,6-dimethoxy-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine is prepared according to the method described in patent WO03 / 000688A1. Manufactured.

(Example 83)
2- {5,6-dimethoxy-1- [3- (4-methylperhydro-1,4-diazepin-1-yl) propyl] -1H-indol-3-yl} -1H-pyrrolo [2,3 -B] pyridine trifluoroacetate a) 2- {5,6-dimethoxy-1- [3- (4-methylperhydro-1,4-diazepin-1-yl) propyl] -1H-indole-3 -Il} -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine trifluoroacetate (0.053 g, 63.9 μmol) and above (Example 82a) Similarly, 2- {5,6-dimethoxy-1- [3- (4-methylperhydro-1,4-diazepin-1-yl) propyl] -1H-indol-3-yl} -1H-pyrrolo [2,3-b] Pyridine is produced It is possible. Thus, 2- {5,6-dimethoxy-1- [3- (4-methylperhydro-1,4-diazepin-1-yl) propyl] -1H-indol-3-yl} -1H-pyrrolo [ 2,3-b] pyridine trifluoroacetate (0.023 g, 45%) is obtained, the properties of which are as follows:

LC / MS analysis: tr = 2.8 min. m / z = 448.30 [M + H] ⁺ .

  b) 2- [1- (3-Iodopropyl) -5,6-dimethoxy-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine (0.04 g, 65 μmol), potassium carbonate (0.027 g; 195 μmol) and 1-methylhomopiperazine (0.022 g; 195 μmol) in the same manner as above (Example 82b) except that 2- {5 6-Dimethoxy-1- [3- (4-methylperhydro-1,4-diazepin-1-yl) propyl] -1H-indol-3-yl} -1- (toluene-4-sulfonyl) -1H- Pyrrolo [2,3-b] pyridine trifluoroacetate can be produced. 2- {5,6-dimethoxy-1- [3- (4-methylperhydro-1,4-diazepin-1-yl) propyl] -1H-indol-3-yl} -1- (toluene-4- Sulfonyl) -1H pyrrolo [2,3-b] pyridine trifluoroacetate (0.053 g; 98%) is obtained and used as such in the next step.

  c) 2- [1- (3-Iodopropyl) -5,6-dimethoxy-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine Is made according to Example 82c.

(Examples 84 to 87)
Step 1: Alkylation The amine specifically listed in the table below is weighed and dissolved in dimethylformamide (concentration 120 μmol / dimethylformamide 0.5 mL).

  Dispense 0.5 mL of each amine solution into a reactor suitable for parallel synthesis, add potassium carbonate (0.017 g / well), and finally 2- [1- (3-iodopropyl) -5,6-dimethoxy. -1H-Indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine (Example 82c) A solution of 40 μmol dimethylformamide (0.5 mL) per reactor Distribute. The calypso reactor is closed and placed at 50 ° C. for 16 hours with orbital shaking. After returning to 20 ° C., the solution obtained above is purified by reverse phase liquid chromatography mass spectrometry (Method B). After evaporation, weighing, dilution and analysis by reverse phase liquid chromatography mass spectrometry (Method A), the expected compound is isolated and used in the next step.

Step 2: Deprotection Each compound obtained above is treated with 21 mL of methanolic potassium hydroxide solution (0.1 g of potassium hydroxide / 1 mL of methanol) at 21 ° C. for 48 hours. The solvent is distilled off under reduced pressure, and the resulting solid is dissolved in dimethyl sulfoxide (0.5 mL). To the resulting solution is added 0.5 mL of 5M aqueous hydrochloric acid and the resulting compound is purified by repeating the reverse phase liquid chromatography mass spectrometry (Method E) twice. Following fractionation and analysis by reverse phase liquid chromatography mass spectrometry (Method A), the following compounds are identified and characterized:

(Example 88)
2- [5,6-dimethoxy-1- (2-methoxyethyl) -1H-indol-3-yl] -1H-pyrrolo [2,3-b] pyridine a) 2- [5,6-dimethoxy-1 -(2-Methoxyethyl) -1H-indol-3-yl] -1H-pyrrolo [2,3-b] pyridine is prepared by the following method.

  2- [5,6-dimethoxy-1- (2-methoxyethyl) -1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine 080 g is added to 3.1 mL of methanolic potassium hydroxide solution (0.1 g / mL; 1.78 M) at a temperature around 20 ° C. The reaction medium is stirred at this same temperature for 5 hours. The reaction medium is heated at 50 ° C. for 4 hours. After cooling, the resulting solid is filtered off through sintered glass and washed twice with 3 mL of methanol and then 5 times with 5 mL of water. The solid is dried in a dryer (35 ° C.) under reduced pressure. There was thus obtained 0.019 g of 2- [5,6-dimethoxy-1- (2-methoxyethyl) -1H-indol-3-yl] -1H-pyrrolo [2,3-b] pyridine, The characteristics are as follows.

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SOd 6, δ value, ppm) 3.29 (s: 3H); 3.73 (t, J = 5 Hz: 2H); 3.87 (s: 3H); 6.90 (s: 3H); 4.37 (wide t, J = 5 Hz: 2H); 6.79 (wide s: 1H); 7.03 (dd, J = 8 and 5 Hz: 1H); 22 (s: 1H); 7.44 (s: 1H); 7.87 (wide d, J = 8 Hz: 1H); 7.87 (s: 1H); 8.03 (dd, J = 5 and 1 .5 Hz: 1 H); 11.79 (wide s: 1 H).

Mass spectrum (EI): m / z = 351 [M + H] ⁺ (reference peak).

  b) 2- [5,6-Dimethoxy-1- (2-methoxyethyl) -1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine Is manufactured by the following method.

  0.01 g of sodium hydride (60%) was added to 2- [5,6-dimethoxy-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b]. To a solution of 0.1 g of pyridine in dehydrated dimethylformamide (2.5 mL) is added an inert argon atmosphere at a temperature around 20 ° C. Stirring is maintained at this temperature for 30 minutes. Add 0.023 mL of bromoethyl methyl ether. The reaction medium is stirred for 16 hours at the same temperature. Add 3 mL of water and 3 mL of ethyl acetate. After separation by settling, the organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue is purified on a flash-pack chromatography cartridge (silica, methylene chloride as eluent). Fractions containing product are concentrated under reduced pressure. 2- [5,6-dimethoxy-1- (2-methoxyethyl) -1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine 082 g is thus obtained, the properties of which are as follows:

Mass spectrum (EI): m / z = 505 [M] ⁺ ; m / z = 350 (reference peak).

  The compound 2- (5,6-dimethoxy-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine is prepared according to the method described in patent WO03 / 000688A1. Manufactured according to.

Example 89
2- [5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] pyridin-2-yl) indol-1-yl] ethanol a) 2- [5,6-dimethoxy-3- (1H -Pyrrolo [2,3-b] pyridin-2-yl) -indol-1-yl] ethanol is prepared by the following method.

  2- {5,6-dimethoxy-3- [1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine was added to 1.65 mL of 5N aqueous potassium hydroxide at a temperature around 20 ° C. 2-yl] indol-1-yl} ethanol is added to a solution of 0.18 g of methanol (10 mL). The reaction medium is refluxed for 4 hours. After cooling, the resulting solid is filtered off through sintered glass and washed twice with 3 mL of methanol and then 5 times with 5 mL of water. The solid is purified by flash-pack chromatography (silica, 95/05 volume ratio methylene chloride / methanol as eluent). 0.045 g of 2- [5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] pyridin-2-yl) -indol-1-yl] ethanol is obtained, the properties of which are as follows: It is.

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ value ppm) 3.80 (unresolved peak: 2H); 3.87 (s: 3H); 3.91 (s: 3H); 26 (wide t, J = 5.5 Hz: 2H); 5.00 (undivided peak: 1H); 6.78 (d, J = 2 Hz: 1H); 7.03 (dd, J = 8 and 5Hz: 7.19 (s: 1H); 7.45 (s: 1H); 7.87 (wide d, J = 8 Hz: 1H); 7.89 (s: 1H); 8.13 (dd, 1H); J = 5 and 1.5 Hz: 1H); 11.78 (wide s: 1H). Mass spectrum (EI): m / z = 337 [M] ⁺ (reference peak).

  b) 2- {5,6-dimethoxy-3- [1- (toluene-4-sulfonyl) -1H-pyrrolo- [2,3-b] pyridin-2-yl] indol-1-yl I ethanol, It is manufactured by the following method.

  2- [5,6-dimethoxy-1- (2-tert-butyldimethylsilyloxyethyl) indole- was added 1.52 mL of tetrabutylammonium fluoride (TBAF) at a temperature around 20 ° C. under an inert argon atmosphere. 3-yl] -1 (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine is added dropwise to a solution of 0.46 g of dehydrated tetrahydrofuran (9.5 mL). The reaction medium is stirred for 6 hours at the same temperature. The reaction medium is concentrated under reduced pressure. The resulting residue is purified by flash chromatography (silica, 98/02 volume ratio methylene chloride / methanol, argon as eluent). Fractions containing product are concentrated under reduced pressure. 0.187 g of 2- {5,6-dimethoxy-3- [1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridin-2-yl] -indol-1-yl} ethanol And its properties are as follows.

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ value ppm) 2.30 (s: 3H); 3.74 (s: 3H); 3.83 (mt: 2H); 3.88 ( 4.30 (t, J = 6 Hz: 2H); 5.00 (undivided peak: 1H); 6.75 (s: 1H); 6.95 (s: 1H); 7.20 (S: 1H); 7.25 (wide d, J = 8 Hz: 2H); 7.31 (dd, J = 8 and 5 Hz 1H); 7.50 (s: 1H); 7.58 (d, J = 8.95 (dd, J = 8 and 1.5 Hz: 1H); 8.37 (dd, J = 5 and 1.5 Hz: 1H).

  c) 2- [5,6-Dimethoxy-1- (2-tert-butyldimethylsilyloxy-ethyl) indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3- b] pyridine) is prepared by the following method.

  0.049 g of sodium hydride (60% product) was added to 2- (5,6-dimethoxy-1H-indol-3-yl] -1- (toluene-4-l) at a temperature around 20 ° C. under an inert argon atmosphere. Sulfonyl) -1H-pyrrolo [2,3-b] pyridine is added to a solution of 0.5 g of dehydrated dimethylformamide (12.5 mL), and stirring is maintained at this temperature for 30 minutes 2-tert-butyldimethylsilyloxyethyl bromide 0.264 mL is added, the reaction medium is stirred for 16 hours at the same temperature, 25 mL of water and 20 mL of ethyl acetate are added, after separation by settling, the organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained was subjected to flash chromatography (silica, 98/02 volume ratio methylene chloride / methanol, argon as eluent). Fractions containing the product are concentrated under reduced pressure 2- [5,6-dimethoxy-1- (2-tert-butyldimethylsilyloxyethyl) indol-3-yl] -1- ( 0.47 g of toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine is thus obtained, the properties of which are as follows:

Mass spectrum (EI): m / z = 605 [M] ⁺ ; m / z = 450 (reference peak).

  The compound 2- (5,6-dimethoxy-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine is prepared according to the method described in patent WO03 / 000688A1. Manufactured according to.

(Example 90)
3- [5,6-Dimethoxy-3- (1H-pyrrolo [2,3-b] pyridin-2-yl) indol-1-yl] propanol a) 3- [5,6-dimethoxy-3- (1 0.24 g of-(toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridin-2-yl) indol-1-yl] propanol and methanolic potassium hydroxide solution (0.1 g / mL; 1 .78 M) 3- [5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] pyridin-2-yl)-by following the procedure described in Example 88a except using 9.3 mL. Indol-1-yl] propanol is produced. After purification by flash-pack chromatography (silica, 98/02 volume ratio methylene chloride / methanol as eluent), 3- [5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] pyridine-2 0.13 g of -yl) indol-1-yl] propanol are obtained, the properties of which are as follows:

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ value ppm) 1.99 (mt: 2H); 3.48 (mt: 2H); 3.88 (s: 3H); 3.92 ( 4.27 (wide t, J = 7 Hz: 2H); 4.66 (wide t, J = 5 Hz: 1H); 6.78 (d, J = 2 Hz: 1H); 7.03 (s: 3H); dd, J = 8 and 5 Hz: 1H); 7.17 (s: 1H); 7.45 (s: 1H); 7.87 (s: 1H); 7.87 (dd, J = 8 and 1). 5 Hz: 1 H); 8.13 (dd, J = 5 and 1.5 Hz: 1 H); 11.73 (undivided peak: 1 H). Mass spectrum (EI): m / z = 351 [M] ⁺ (reference peak).

  b) 2- [5,6-Dimethoxy-1- (3-tert-butyldimethylsilyloxypropyl) indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b By following the procedure described in Example 89b except that 0.605 g of pyridine and 1.95 mL of tetrabutylammonium fluoride (TBAF) were used, 3- {5,6-dimethoxy-3- [1- (toluene-4 -Sulfonyl) -1H-pyrrolo [2,3-b] pyridin-2-yl] indol-1-yl} propanol and 2- [5,6-dimethoxy-1- (3-fluoropropyl) indol-3-yl ] -1- (Toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine is produced. After purification by flash chromatography (silica, 98/02 volume ratio methylene chloride / methanol, argon as eluent), 3- {5,6-dimethoxy-3- [1- (toluene-4-sulfonyl) -1H-pyrrolo 0.243 g of [2,3-b] pyridin-2-yl] indol-1-yl} propanol are obtained, the properties of which are as follows:

Mass spectrum (EI): m / z = 505 [M] ⁺ (reference peak).

  And 0.046 g of 2- [5,6-dimethoxy-1- (3-fluoropropyl) indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine was obtained. The properties obtained are as follows.

Mass spectrum (EI): m / z = 507 [M] ⁺ (reference peak).

  c) 0.285 mL 2-tert-butyldimethylsilyloxypropyl bromide and 2- [5,6-dimethoxy-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2, 3-b] By following the procedure described in Example 89c except using 0.5 g of pyridine and 0.049 g of sodium hydride (60% product), 2- [5,6-dimethoxy-1- (3-tert -Butyldimethylsilyloxy-propyl) indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine is prepared. After purification by flash chromatography (silica, 98/02 volume ratio methylene chloride / methanol, argon as eluent), 2- [5,6-dimethoxy-1- (3-tert-butyldimethylsilyloxypropyl) indole-3 0.65 g of -yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine is obtained, the properties of which are as follows:

Mass spectrum (EI): m / z = 619 [M] ⁺ (reference peak).

  The compound 2- (5,6-dimethoxy-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine is prepared according to the method described in patent WO03 / 000688A1. Manufactured according to.

(Example 91)
2- [1- (3-Fluoropropyl) -5,6-dimethoxy-1H-indol-3-yl] -1H-pyrrolo [2,3-b] pyridine 2- [5,6-dimethoxy-1- ( Implemented except using 0.042 g of 3-fluoropropyl) indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine and 1.63 mL of 5N aqueous potassium hydroxide. By following the procedure described in Example 88a, 2- [1- (3-fluoropropyl) -5,6-dimethoxy-1H-indol-3-yl] -1H-pyrrolo [2,3-b] pyridine was prepared. To do. After purification by flash-pack chromatography (silica, 98/02 volume ratio methylene chloride / methanol as eluent), 2- [1- (3-fluoropropyl) -5,6-dimethoxy-1H-indol-3-yl ] -1H-pyrrolo [2,3-b] pyridine (0.008 g) is obtained, and the characteristics are as follows.

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ subthia ppm) 2.22 (dt, J = 26 and 6.5 Hz: 2H); 3.88 (s: 3H); 3.91 ( 4.33 (t, J = 6.5 Hz: 2H); 4.52 (dt, J = 48 and 6.5 Hz: 2H); 6.80 (wide d, J = 2 Hz: 1H); 7.04 (dd, J = 8 and 5 Hz: 1H); 7.18 (s: 1H); 7.45 (s: 1H); 7.88 (wide dd, J = 8 and 1.5 Hz: 1H); 7.89 (s: 1H); 8.14 (dd, J = 5 and 1.5 Hz: 1H); 11.78 (wide s: 1H).

Mass spectrum (EI): m / z = 353 [M] ⁺ (reference peak).

(Example 92)
3- [5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] pyridin-2-yl) indol-1-yl] propionic acid a) 3- [5,6-dimethoxy-3- ( 1 g of methyl 1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridin-2-yl) indol-1-yl] propionate and methanolic potassium hydroxide solution (0.1 g / mL; 1.78M) 3- [5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] pyridin-2-yl) -indole by following the procedure described in Example 88a except using 74 mL. -1-yl] propionic acid is produced. 0.601 g of 3- [5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] pyridin-2-yl) indol-1-yl] propionic acid is obtained, the properties of which are as follows: It is.

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ value ppm) 2.82 (t, J = 6.5 Hz: 2H); 3.88 (s: 3H); 3.90 (s: 3H 4.44 (t, J = 6.5 Hz: 2H); 6.78 (wide d, J = 2 Hz: 1H); 7.03 (dd, J = 8 and 5 Hz: 1H); 7.22 ( 7.44 (s: 1H); 7.86 (wide d, J = 8 Hz: 1H); 7.87 (s: 1H); 8.13 (wide dd, J = 5 and 1). 5 Hz: 1H); 11.78 (wide s: 1H).

Mass spectrum (EI): m / z = 365 [M] ⁺ (reference peak).

  b) methyl 3- {5,6-dimethoxy-3- [1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridin-2-yl] indol-1-yl} propionate It is manufactured by the following method.

  2- (5,6-dimethoxy-1H-indol-3-yl] -1- (toluene-4) was added 0.34 g of potassium carbonate and 0.243 mL of methyl acrylate under an inert argon atmosphere at a temperature around 20 ° C. -Sulfonyl) -1H-pyrrolo [2,3-b] pyridine is added dropwise to a solution of 1 g of dehydrated dimethylformamide (20 mL), the reaction medium is stirred for 16 hours at the same temperature, 20 mL of water and 20 mL of ethyl acetate are added. After separation, the organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure, and after purification by flash chromatography (silica, methylene chloride, argon as eluent), the fraction containing the product is concentrated under reduced pressure. 3- {5,6-dimethoxy-3- [1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridy 2-yl] indol-1-yl} methyl propionate 1g is obtained by doing so, the characteristics are as follows.

Mass spectrum (EI): EI: m / z = 533 [M] ⁺ (reference peak), m / z = 378.

  The compound 2- [5,6-dimethoxy-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine is prepared according to the method described in Patent WO03 / 000688A1. Manufactured according to.

(Example 93)
3- [5,6-Dimethoxy-3- (1H-pyrrolo [2,3-b] pyridin-2-yl) indol-1-yl] -1-morpholin-4-yl-propan-1-one 3- [5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] pyridin-2-yl) -indol-1-yl] -1-morpholin-4-ylpropan-1-one Manufactured by the method.

  0.036 g of O- (1H-benzotriazol-1-yl) -N, N, N ′, N′-tetra-methyluronium hexafluorophosphate was prepared at a temperature of about 20 ° C. under an inert argon atmosphere. [5,6-Dimethoxy-3- (1H-pyrrolo [2,3-b] pyridin-2-yl) indol-1-yl] propionic acid is added to a solution of 0.035 g in dimethylformamide (3 mL). The reaction medium is stirred at this temperature for 1 hour. Add 0.01 mL of morpholine and then 0.017 mL of diisopropylethylamine. After stirring for 3 hours at the same temperature, 10 mL of water and 10 mL of ethyl acetate are added. After separation by settling, the organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue is purified by flash-pack chromatography (silica, 98/02 volume ratio methylene chloride / methanol as eluent). Fractions containing product are concentrated under reduced pressure. 3- [5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] pyridin-2-yl) indol-1-yl] -1-morpholin-4-ylpropan-1-one 0.025 g Is obtained and its properties are as follows.

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ value ppm): 2.90 (t, J = 6.5 Hz: 2H); 3.30 to 3.55 (mt: 8H); 8 (s: 3H); 3.90 (s: 3H); 4.47 (wide t, J = 6.5 Hz: 2H); 6.78 (d, J = 2 Hz: 1H); 7.03 (dd , J = 8 and 5 Hz: 1H); 7.19 (s: 1H); 7.44 (s: 1H); 7.86 (s: 1H); 7.87 (wide d, J = 8 Hz: 1H) 8.13 (dd, J = 5 and 1.5 Hz: 1 H); 11.78 (wide s: 1 H). Mass spectrum (EI): m / z = 434 [M] ⁺ (reference peak).

(Example 94)
2- [5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] pyridin-2-yl) indol-1-yl] -1- (4-hydroxypiperidin-1-yl) -ethanone a ) Except using 0.2 g of 2- [5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] pyridin-2-yl) indol-1-yl] acetic acid and 0.07 g of 4-hydroxypiperidine Followed the procedure described in Example 93 to give 2- [5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] pyridin-2-yl) -indol-1-yl] -1- (4-Hydroxypiperidin-1-yl) ethanone is produced. After purification by flash-pack chromatography (silica, 98/02 volume ratio methylene chloride / methanol as eluent), 2- [5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] pyridine-2 -Il) -Indol-1-yl] 1- (4-hydroxypiperidin-1-yl) ethanone 0.096 g is obtained, the properties of which are as follows.

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value): 1.20 to 1.55 (mt: 2H); 1.70 to 1.95 (mt: 2H); 3.12 and 3 .20-3.45 (each wide t, J = 11 Hz and mt: 2H in total); 3.75-4.00 (mt: 2H); 3.78 (mt: 1H); 3.84 (s: 3H); 3.91 (s: 3H); 4.81 (d, J = 3.5 Hz: 1H); 5.21 (limited AB, J = 16.5 Hz: 2H); 6.79 (d, J 7.03 (dd, J = 8 and 5 Hz: 1H); 7.10 (s: 1H); 7.46 (s: 1H); 7.76 (s: 1H); 88 (dd, J = 8 and 1.5 Hz: 1H); 8.13 (dd, J = 5 and 1.5 Hz: 1H); 6 (broad s: 1H).

Mass spectrum (EI): m / z = 434 [M] ⁺ (reference peak).

  b) 2- {5,6-dimethoxy-3- [1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridin-2-yl] indol-1-yl} tert-butyl acetate By following the procedure described in Example 88a but using 1 g and 73 mL of methanolic potassium hydroxide solution (0.1 g / mL; 1.78 M), 2- [5,6-dimethoxy-3- (1H-pyrrolo) [2,3-b] pyridin-2-yl) -indol-1-yl] acetic acid is prepared. 0.701 g of 2- [5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] pyridin-2-yl) indol-1-yl] acetic acid was obtained, the properties of which were as follows: is there.

Mass spectrum (EI): m / z = 351 [M] ⁺ (reference peak).

  c) 1.91 g of tert-butyl bromoacetate and 2- (5,6-dimethoxy-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine By following the procedure described in Example 89c but using 4 g, 2- {5,6-dimethoxy-3- [1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine- 2-yl] indol-1-yl} -tert-butyl acetate is prepared: 2- {5,6-dimethoxy-3- [1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b ] 4.5 g of tert-butyl acetate is obtained, the properties of which are as follows:

Mass spectrum (CI): m / z = 562 [M + H] ⁺ (reference peak).

(Example 95)
2- [5,6-Dimethoxy-3- (1H-pyrrolo [2,3-b] pyridin-2-yl) indol-1-yl] -1-thiazolidin-3-ylethanone 2- [5,6-dimethoxy By following the procedure described in Example 93 except that 0.2 g of -3- (1H-pyrrolo [2,3-b] pyridin-2-yl) indol-1-yl] acetic acid and 0.061 g of thiazolidine are used. 2- [5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] pyridin-2-yl) -indol-1-yl] -1-thiazolidin-3-ylethanone is prepared. 0.133 g of 2- [5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] pyridin-2-yl) indol-1-yl] -1-thiazolidin-3-ylethanone was obtained, which The characteristics are as follows.

¹ H NMR spectrum (400 MHz, (CD ₃ ) ₂ SO d6, temperature at 373 K, δ ppm value): 3.16 (unresolved peak: 2H); 3.85 to 3.95 (mt: 2H); 86 (s: 3H); 3.90 (s: 3H); 4.66 (wide s: 2H); 5.16 (s: 2H); 6.72 (d, J = 1.5 Hz: 1H); 7.01 (dd, J = 8 and 4.5 Hz: 1H); 7.11 (s: 1H); 7.49 (s: 1H); 7.76 (s: 1H); 7.86 (dd, J = 8 and 1.5 Hz: 1H); 8.13 (dd, J = 4.5 and 1.5 Hz: 1H); 11.45 (undivided peak: 1H).

Mass spectrum (EI): m / z = 422 [M] ⁺ (reference peak).

(Example 96)
4-{[5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] -pyridin-2-yl) indol-1-yl] acetyl} -1-methylpiperazin-2-one 2- [ Using 0.1 g of 5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] -pyridin-2-yl) indol-1-yl] acetic acid and 0.039 g of 1-methylpiperazin-2-one Except following the procedure described in Example 93 to give 4-{[5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] pyridin-2-yl) -indol-1-yl] acetyl. } -1-Methylpiperazin-2-one is produced. 0.088 g of 4-{[5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] pyridin-2-yl) indol-1-yl] acetyl} -1-methylpiperazin-2-one The properties obtained are as follows.

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value). At room temperature, a 50/50 mixture of rotamers is observed.

  * 2.94 and 2.96 (2s: 3H total); 3.39 and 3.54 (2mt: 2H total); 3.75 and 3.91 (2mt: 2H total); 3.85 (s: 3H) 3.91 (s: 3H); 4.07 and 4.34 (wide 2s: 2H total); 5.25 and 5.30 (wide 2s: 2H total); 6.79 (d, J = 1) 7.04 (dd, J = 8 and 5 Hz: 1H); 7.13 and 7.15 (wide 2s: 1H total); 7.46 (s: 1H); 7.71 and 7 .74 (2s: 1H total); 7.88 (wide d, J = 8 Hz: 1H); 8.14 (dd, J = 5 and 1.5 Hz: 1H); 11.79 (undivided peak: 1H) .

Mass spectrum (EI): m / z = 447 [M] ⁺ (reference peak).

(Example 97)
4-chloro-2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyridine a) 4-chloro-2- (5,6- Using 2.8 g of dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine and 25.5 mL of 5N aqueous potassium hydroxide solution Except that the procedure described in Example 89a is followed to give 4-chloro-2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyridine. Manufacturing. 1.81 g of 4-chloro-2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyridine is obtained, which has the following properties: Street.

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value) 3.86 (s: 3H); 3.89 (s: 3H); 3.92 (s: 3H); 6.73 (s 7.16 (d, J = 5 Hz: 1 H); 7.17 (s: 1 H); 7.46 (s: 1 H); 7.86 (s: 1 H); 8.09 (d, J = 5 Hz: 1H); 12.16 (undivided peak: 1H).

Mass spectrum (EI): m / z = 341 [M] ⁺ (reference peak).

  b) 7.1 g of 4-chloro-2- (5,6-dimethoxy-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine and iodine 4-chloro-2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene) by following the procedure described in Example 89c except using 1.10 mL of methyl iodide. -4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine is prepared. After purification by flash chromatography (silica, 40/60 volume ratio ethyl acetate / cyclohexane, argon as eluent) 4-chloro-2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) 5.69 g of -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine is obtained, the properties of which are as follows.

Mass spectrum (EI): m / z = 495 [M] ⁺ m / z = 340 (reference peak).

  c) 4-Chloro-2- (5,6-dimethoxy-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine is prepared by the following method. Manufactured by.

  67 mL of saturated aqueous sodium bicarbonate solution and 1.34 g of tetrakis (triphenylphosphine) palladium, 10 g of 1- (toluene-4-sulfonyl) -1H-2-iodo-4-chloropyrrolo [2,3-b] pyridine, dehydrated dimethyl To a solution of 245 mL formamide and 7.42 g 1-tert-butyloxycarbonyl-5,6-dimethoxyindole-3-boronic acid is added at a temperature around 20 ° C. under an inert argon atmosphere. The reaction medium is heated at 130 ° C. for 45 minutes. After cooling, the reaction medium is concentrated under reduced pressure. The oil obtained is taken up with 300 mL of water and 300 mL of ethyl acetate. After separation by settling, the organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (silica, 40/60 volume ratio ethyl acetate / cyclohexane, argon as eluent). Fractions containing product are concentrated under reduced pressure. 7.52 g of 4-chloro-2- (5,6-dimethoxy-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine was The properties obtained are as follows.

Mass spectrum (EI): m / z = 481 [M] ⁺ ; m / z = 326 (reference peak).

  Compounds 1- (toluene-4-sulfonyl) -1H-2-iodo-4-chloropyrrolo [2,3-b] pyridine and 1-tert-butyloxy-carbonyl-5,6-dimethoxyindole-3-boronic acid Manufactured according to the method described in patent WO03000688A1.

(Example 98)
2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyridine-4-carbonitrile a) 2- (5,6-dimethoxy-1 -Methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyridine-4-carbonitrile can be prepared by the following method.

  2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine-4-carbonitrile A suspension of 14 g of 5N aqueous potassium hydroxide (1.3 mL) and methanol (5 mL) is brought to around 60 ° C. for about 30 minutes. After returning to about 20 ° C., the insoluble material is dried with a filter and washed with water until a neutral pH is obtained. The insoluble material is purified by flash chromatography on a silica column [eluent: methylene chloride / methanol (98/2 volume ratio)]. 0.05 g of 2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyridine-4-carbonitrile is obtained in the form of a solid, The characteristics are as follows.

  Silica TLC [eluent: methylene chloride / methanol (98/2 volume ratio)] Rf = 0.17.

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value): 3.87 (s: 3H); 3.89 (s: 3H); 3.92 (s: 3H); 6.87 ( 7.17 (s: 1H); 7.44 (wide d, J = 5 Hz: 1H); 7.49 (wide s: 1H); 7.95 (s: 1H); 25 (d, J = 5 Hz: 1H); 12.44 (undivided peak: 1H).

Mass spectrum (EI): m / z = 332 [M] ⁺ (reference peak); m / z = 317 [M—CH ₃ ] ⁺ ; m / z = 289; [m / z = 317−CO] ⁺ .

  b) 2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine-4-carbonitrile Can be manufactured by the following method.

  4-chloro 2- (5,6-dimethoxy-1-methyl-1H-indole obtained by degassing 0.029 g of [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) with argon for about 15 minutes -3-yl) -1- (toluene-4sulfonyl) -1H-pyrrolo [2,3-b] pyridine 0.2 g, zinc cyanide 0.084 g and zinc powder 0.013 g N, N-dimethylacetamide ( 20 mL) to the suspension. The reaction mixture is allowed to reach about 150 ° C. for about 2 hours 30 minutes. After returning to approximately 20 ° C., the reaction mixture is filtered through Celite and the insoluble material is washed with 100 mL of methylene chloride. The filtrate is washed 3 times with 100 L of water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (13 kPa). The residue is purified by flash chromatography on a silica column [eluent: cyclohexane / ethyl acetate (50/50 volume ratio)]. 2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine-4-carbonitrile 14 g are obtained in the form of a rake, the properties of which are as follows:

  Silica TLC [eluent: cyclohexane / ethyl acetate (50/50 volume ratio)] = Rf 0.40.

Mass spectrum (EI): m / z = 486 [M] ⁺ ; m / z = 331 [M-C7H702S] ⁺ (reference peak); m / z = 316 [331-CH ₃ ] ⁺ −; m / z = 155 [C ₇ H ₇ O ₂ S ⁺ ]; m / z = 91 [C ₇ H ₇ ⁺ ].

  4-chloro-2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine was Prepared according to the method described in example 97b.

Example 99
4-chloro-2- [5,6-dimethoxy-1- (2-morpholin-4-ylethyl) -1H-indol-3-yl] -1H-pyrrolo [2,3-b] pyridine a) 4-chloro 2- [5,6-Dimethoxy-1- (2-morpholin-4-ylethyl) -1H-indol-3-yl] -1H-pyrrolo [2,3-b] pyridine is produced by the following method. be able to.

  4-Chloro-2- [5,6-dimethoxy-1- (2-morpholin-4-ylethyl) -1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2, 3-b] A solution of 0.54 g of pyridine and 1.8 g of potassium hydroxide in methanol (18 mL) is brought to about 60 ° C. for about 2 hours. After cooling to about 20 ° C., the precipitate is filter-dried, washed twice with 3 mL of methanol and 3 times with 5 mL of water, and vacuum-dried in a dryer at a temperature around 40 ° C. for about 8 hours (13 kPa). 0.241 g of 4-chloro-2- [5,6-dimethoxy-1- (2-morpholin-4-ylethyl) -1H-indol-3-yl] -1H-pyrrolo [2,3-b] pyridine is solid. The following characteristics are obtained.

  Melting point: 240 ° C. (Kofler bench).

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value): 2.48 (t, J = 4.5 Hz: 4H); 2.74 (t, J = 6.5 Hz: 2H); 3 .49 (t, J = 4.5 Hz: 4H); 3.87 (s: 3H); 3.89 (s: 3H); 4.32 (wide t, J = 6.5 Hz: 2H); 71 (s: 1H); 7.14 (d, J = 5 Hz: 1H); 7.20 (s: 1H); 7.42 (s: 1H); 7.92 (s: 1H); 8.07 (D, J = 5 Hz: 1H); 12.13 (undivided peak: 1H).

Mass spectrum (EI): m / z = 440 [M] ⁺ (reference peak); m / z = 340 [M−C ₅ H ₁₀ NO] ⁺ ; m / z = 100 [C ₅ H ₁₀ NO] ⁺ .

  b) 4-Chloro-2- [5,6-dimethoxy-1- (2-morpholin-4-ylethyl) -1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [ 2,3-b] pyridine can be prepared by the following method.

  4-chloro-2- (5,6-dimethoxy-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] -pyridine 1 g, 4- (2 A suspension of 0.655 g of chloroethyl) morpholine hydrochloride and 1.11 g of potassium carbonate in dimethylformamide (10 mL) is heated at approximately 95 ° C. for approximately 3 hours. After cooling to a temperature around 20 ° C., the reaction mixture is taken up in 20 mL of water and extracted three times with 100 mL of ethyl acetate. The combined organic phases are washed with 100 mL of saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (13 kPa). The residue is purified by flash chromatography on a silica column [eluent: cyclohexane / ethyl acetate (90/10 volume ratio)]. 4-Chloro-2- [5,6-dimethoxy-1- (2-morpholin-4-ylethyl) -1H-indol-3-yl] -1- (toluene-4sulfonyl) -1H-pyrrolo [2,3 -B] 0.54 g of pyridine is obtained in the form of a solid, the properties of which are as follows:

  Silica TLC [eluent: methylene chloride / methanol (98/2 volume ratio)] Rf = 0.18.

Mass spectrum (EI): m / z = 594 [M] ⁺ ; m / z = 481 [M-C ₆ H ₁₁ NO] ⁺ ; m / z = 439 [M-C ₇ H ₇ O ₂ S] ⁺ ; m / z = 326 [m / z = 481-C ₇ H ₇ O ₂ S] ⁺ ; m / z = 100 [C ₅ H ₁₀ NO ⁺ ] (reference peak).

  4-Chloro-2- (5,6-dimethoxy-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine is described in Example 97c. Manufactured according to the method of

(Example 100)
2- (1- {2- [3- (4-Chloro-1H-pyrrolo [2,3-b] pyridin-2-yl) -5,6-dimethoxyindol-1-yl] ethyl} piperidine-4- Yl) ethanol a) 2- [1- (2- {3- [4-chloro-1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridin-2-yl] -5, 6-Dimethoxyindol-1-yl} ethyl) piperidin-4-yl] ethanol in the same manner as in Example 99a except that 0.160 g of ethanol and 0.58 g of potassium hydroxide in methanol (10 mL) were used. -{2- [3- (4-Chloro-1H-pyrrolo [2,3-b] pyridin-2-yl) -5,6-dimethoxyindol-1-yl] ethyl} piperidin-4-yl) ethanol Can be manufactured. After flash chromatography on a silica column [eluent: methylene chloride / methanol (80/20 volume ratio)], thus 2- (1- {2- [3- (4-chloro-1H-pyrrolo [2, 3-b] pyridin-2-yl) -5,6-dimethoxyindol-1-yl] ethyl} piperidin-4-yl) ethanol is obtained in the form of a solid, the properties of which are as follows: is there.

  Melting point: 200 ° C. (Kefler stand).

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value) 1.00 to 1.25 (mt: 2H); 1.25 to 1.40 (mt: 3H); 1.63 (very Wide d, J = 13 Hz: 2H); 1.99 (wide t, J = 11.5 Hz: 2H); 2.70 (t, J = 6.5 Hz: 2H); 2.93 (wide d, J = 11.5 Hz: 2H); 3.43 (undivided peak: 2H); 3.88 (s: 3H); 3.90 (s: 3H); 4.32 (mt: 3H); 6.71 (wide) 7.15 (d, J = 5 Hz: 1H); 7.20 (s: 1H); 7.42 (s: 1H); 7.92 (s: 1H); 8.07 (d) J = 5 Hz: 1H); 12.16 (undivided peak: 1H). Mass spectrum (EI): m / z = 482 [M] ⁺ ; m / z = 142 [C ₈ H ₁₆ NO] ⁺ (reference peak).

  b) 2- [1- (2- {3- [4-Chloro-1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridin-2-yl] -5,6-dimethoxy Indol-1-yl} ethyl) piperidin-4-yl] ethanol can be prepared by the following method.

  4-Chloro-2- [1- (2-iodoethyl) -5,6-dimethoxy-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] A suspension of 0.280 g of pyridine, 0.061 g of potassium carbonate and 0.114 g of 2-piperidin-4-ylethanol in acetonitrile (30 mL) is brought to a temperature around 60 ° C. After heating at this temperature for about 5 hours, 0.061 g of potassium carbonate and 0.114 g of 2-piperidin-4-ylethanol are added again and the mixture is stirred at this temperature for about 2 hours. After returning to a temperature close to 20 ° C., the mixture is concentrated to dryness under reduced pressure (13 kPa), taken up with 50 ml of water and extracted three times with 40 ml of methylene chloride. The combined organic phases are dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (13 kPa). The residue is purified by flash chromatography on a silica column [eluent: methylene chloride / methanol (95/5 volume ratio)]. 2- [1- (2- {3- [4-Chloro-1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridin-2-yl] -5,6-dimethoxyindole- 0.16 g of 1-yl} ethyl) piperidin-4-yl] ethanol is obtained in the form of an oil, the properties of which are as follows:

Mass spectrum (EI): m / z = 636 [M] ⁺ ; m / z = 481 [M−C ₇ H ₇ O ₂ S] ⁺ ; m / z = 142 [C ₈ H ₁₆ NO] ⁺ (reference peak ).

  c) 4-Chloro-2- [1- (2-iodoethyl) -5,6-dimethoxy-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3- b] Pyridine can be produced by the following method.

  4-Chloro-2- [1- (2-chloroethyl) -5,6-dimethoxy-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] A suspension of 0.760 g pyridine and 0.315 g sodium iodide in 2-butanone (70 mL) is refluxed for about 24 hours. The reaction mixture is evaporated to dryness under reduced pressure (13 kPa), taken up with 50 mL of water and extracted three times with 50 mL of ethyl acetate. The combined organic phases are dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (13 kPa). 4-Chloro-2- [1- (2-iodoethyl) -5,6-dimethoxy-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] 0.98 g of pyridine is obtained in the form of a yellow oil, the properties of which are as follows:

  Silica TLC [eluent: methylene chloride / ethyl acetate (90/10 volume ratio)] Rf = 0.71.

Mass spectrum (EI): m / z = 635 [M] ⁺ (reference peak); m / z = 480 [M−C ₇ H ₇ O ₂ S] ⁺ ; m / z = 353 [480-I] ⁺ ; ^{_{m / z = 338 [353-}} CH 3] +; m / z = 91 [C 7 H 7] +.

  d) 4-chloro-2- [1- (2-chloroethyl) -5,6-dimethoxy-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3- b] Pyridine can be produced by the following method.

  0.79 g of potassium hydroxide and 0.61 g of potassium carbonate were added to 4-chloro-2- (5,6-dimethoxy-1H-indol-3-yl) -1- (toluene-4sulfonyl) -1H-pyrrolo [2 , 3-b] Add 1 g of pyridine and 0.013 g of tetrabutylammonium bromide to a solution of 1,2-dichloroethane (25 mL). The resulting suspension is brought to approximately 50 ° C. for about 5 hours. After returning to a temperature close to 20 ° C. and stirring at this temperature for about 16 hours, the reaction mixture is filtered through celite and the insoluble material is washed with 10 mL of methylene chloride three times. The filtrate is washed 3 times with 50 mL of water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The residue is purified by flash chromatography on a silica column [eluent: cyclohexane / ethyl acetate (75/25 volume ratio)]. 4-Chloro-2- [1- (2-chloroethyl) -5,6-dimethoxy-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] 0.62 g of pyridine is obtained in the form of a solid, the properties of which are as follows:

  Silica TLC [eluent: cyclohexane / ethyl acetate (50/50 volume ratio)] Rf = 0.41.

Mass spectrum (EI): m / z = 543 [M] ⁺ ; m / z = 388 [M−C ₇ H ₇ O ₂ S] ⁺ (reference peak); m / z = 91 [C ₇ H ₇ ] ⁺ .

  4-Chloro-2- (5,6-dimethoxy-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine is described in Example 97c. Manufactured according to the method of

(Example 101)
4-Chloro-2- {5,6-dimethoxy-1- [2- (4-methylpiperazin-1-yl) ethyl] -1H-indol-3-yl} -1H-pyrrolo [2,3-b] Pyridine a) 4-chloro-2- {5,6-dimethoxy-1- [2- (4-methylpiperazin-1-yl) ethyl] -1H-indol-3-yl} -1- (toluene-4- 4-Chloro-2-yl-2-H-pyrrolo [2,3-b] pyridine in the same manner as in Example 100a, except that 0.2 g of potassium and 0.65 g of potassium hydroxide in methanol (7 mL) were used. {5,6-dimethoxy-1- [2- (4-methylpiperazin-1-yl) ethyl] -1H-indol-3-yl} -1H-pyrrolo [2,3-b] pyridine can be produced. it can. After flash chromatography on a silica column [eluent: methylene chloride / methanol (80/20 volume ratio)], 4-chloro-2- {5,6-dimethoxy-1- [2- (4-methylpiperazine-1 -Yl) ethyl] -1H-indol-3-yl} -1H-pyrrolo [2,3-b] pyridine 0.05 g is thus obtained in solid form, the properties of which are as follows.

  Melting point: 192 ° C. (Kefler stand).

¹ H NMR spectrum (300 MHz, (CD ₃ ) _2SO d6, δ ppm value): 2.16 (s: 3H); 2.33 (undivided peak: 4H); 2.40 to 2.55 (mt: 4H) 2.74 (wide t, J = 6.5 Hz: 2H); 3.88 (s: 3H); 3.91 (s: 3H); 4.30 (wide t, J = 6.5 Hz: 2H); 6.71 (wide s: 1H); 7.15 (d, J = 5 Hz: 1H); 7.20 (s: 1H); 7.43 (s: 1H); 7.93 (s: 1H) 8.08 (d, J = 5 Hz: 1H); 12.14 (undivided peak: 1H).

Mass spectrum (EI): m / z = 453 [M] ⁺ ; m / z = 113 [C ₆ H ₁₃ N ₂ ] ⁺ ; (reference peak).

m / z = 70 [C ₄ H ₈ N] ⁺ .

  b) 4-Chloro-2- [1- (2-iodoethyl) -5,6-dimethoxy-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3- b] 4-chloro-2- {5,6 in the same manner as in Example 100b except that 0.98 g of pyridine, 0.21 g of potassium carbonate and 0.31 g of 1-methylpiperazine were used in acetonitrile (100 mL). -Dimethoxy-1- [2- (4-methylpiperazin-1-yl) ethyl] -1H-indol-3-yl} -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] Pyridine can be produced. After flash chromatography on a silica column [eluent: methylene chloride / methanol (90/10 volume ratio)], 4-chloro-2- {5,6-dimethoxy-1- [2- (4-methylpiperazine-1) -Yl) ethyl] -1H-indol-3-yl} -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine is thus obtained in the form of an oil. Its characteristics are as follows.

Mass spectrum (EI): m / z = 607 [M] ⁺ ; m / z = 452 [M−C ₇ H ₇ O ₂ S] ⁺ ;
m / z = 113 [C ₆ H ₁₃ N ₂ ] ⁺ (reference peak); m / z = 70 [C ₄ H ₈ N] ⁺ .

(Example 102)
2- {5,6-dimethoxy-1- [2- (4-methylpiperazin-1-yl) ethyl] -1H-indol-3-yl} -1H-pyrrolo [2,3-b] pyridine-4- Carbonitrile 2- {5,6-dimethoxy-1- [2- (4-methylpiperazin-1-yl) ethyl] -1H-indol-3-yl} -1H-pyrrolo [2,3-b] pyridine- 4-carbonitrile can be produced by the following method.

  4-Chloro-2- (5,6-dimethoxy-1-methyl-1H-) obtained by degassing 0.036 g of [1,1′-bis (diphenyl-phosphino) ferrocene] palladium (II) with argon for about 15 minutes. Indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine 0.3 g, zinc cyanide 0.104 g and zinc powder 0.016 g N, N-dimethyl Add to a suspension of acetamide (20 mL). The reaction mixture is allowed to elapse for about 1 hour at a temperature around 150 ° C. After returning to approximately 20 ° C. and stirring the mixture for 18 hours, the reaction mixture is filtered through Celite and the insoluble material is washed with 100 mL of methylene chloride. The filtrate is washed twice with 100 mL of water and then with 100 mL of saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (13 kPa). The residue is purified by flash chromatography on a silica column [eluent: methylene chloride / methanol (90/10 volume ratio)]. 2- {5,6-dimethoxy-1- [2- (4-methylpiperazin-1-yl) ethyl] -1Hindol-3-yl} -1H-pyrrolo [2,3-b] pyridine-4-carbo 0.08 g of nitrile is obtained in the form of a solid, the properties of which are as follows:

  Melting point: 196 ° C. (Kefler stand).

¹ H NMR spectrum (300 MHz, (CD ₃ ) _2SO d6, δ ppm value): 2.17 (s: 3H); 2.34 (undivided peak: 4H); 2.40 to 2.55 (mt: 4H) 2.75 (t, J = 6.5 Hz: 2H); 3.89 (s: 3H); 3.92 (s: 3H); 4.33 (wide t, J = 6.5 Hz: 2H); 6.98 (d, J = 1.5 Hz: 1H); 7.23 (s: 1H); 7.45 (d, J = 5 Hz: 1H); 7.49 (s: 1H); 8.03 ( s: 1H); 8.26 (d, J = 5 Hz: 1H); 12.43 (wide s: 1H).

Mass spectrum (EI): m / z = 444 [M] ⁺ ; m / z = 113 [C ₆ H ₁₃ N ₂ ] ⁺ (reference peak); m / z = 70 [C ₄ H ₈ N] ⁺ .

(Example 103)
5-chloro-2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyridine a) 5-chloro-2- (5,6- Dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyridine can be produced by the following method.

  1-methylpyrrolidin-2-one of 0.44 g of 5-chloro-3- (5,6-dimethoxy-1-methyl-1H-indol-3-ylethynyl) pyridin-2-ylamine and 0.58 g of potassium tert-butoxide The (25 mL) suspension is heated at a temperature around 70 ° C. for about 4 hours 30 minutes. The mixture is concentrated to dryness under reduced pressure (13 kPa). The residue is taken up with 40 mL of water and the pH of the suspension obtained by adding glacial acetic acid is brought to about 4-5. After stirring for about 10 minutes, the solid is filter dried, washed 3 times with 5 mL of water and air dried. After recrystallization from 160 mL of propan-1-ol, 5-chloro-2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyridine 0 .28 g is obtained in the form of a beige solid, the properties of which are as follows:

  Melting point: 282 ° C. (Bucchi capillary).

¹ H NMR spectrum (300 MHz, (CD ₃ ) _2SO d6, δ ppm value) 3.84 (s: 3H); 3.88 (s: 3H); 3.89 (s: 3H); 6.76 (wide s 7.14 (s: 1H); 7.42 (s: 1H); 7.81 (s: 1H); 7.91 (d, J = 3 Hz: 1H); 8.09 (d, J = 3 Hz: 1H); 11.99 (undivided peak: 1H).

Mass spectrum (EI): m / z = 341 [M] ⁺ (reference peak); m / z = 326 [M-CH ₃ ] ⁺ .

  b) 5-Chloro-3- (5,6-dimethoxy-1-methyl-1H-indol-3-ylethynyl) pyridin-2-ylamine can be prepared by the following method.

  0.43 g of 5-chloro-3-ethynyl-pyridin-2-ylamine, 0.6 g of 3-iodo-5,6-dimethoxy-1-methyl-1H-indole (Example 103-f), and copper iodide 0 0.072 g of a suspension in a mixture of 60 mL of triethylamine and 30 mL of dimethylformamide is degassed with argon for 15 minutes. 0.066 g of bis (triphenylphosphine) palladium (II) chloride is added to the above suspension. The mixture is stirred at approximately 20 ° C. for about 6 hours; 0.075 g of 5-chloro-3-ethynylpyridin-2-ylamine is added and the mixture is stirred at this same temperature for 2 days. The mixture is concentrated to dryness under reduced pressure (13 kPa). The residue is taken up with 100 ml of water and extracted three times with 100 ml of methylene chloride. The organic phases are combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure (13 kPa). The residue is purified by flash chromatography on a silica column [eluent: cyclohexane / ethyl acetate (50/50 volume ratio)]. 0.44 g of 5-chloro-3- (5,6-dimethoxy-1-methyl-1H-indol-3-ylethynyl) pyridin-2-ylamine is thus obtained in solid form, which has the following properties Street.

  Melting point: 192 ° C. (Kefler stand).

Mass spectrum (EI): m / z = 341 [M] ⁺ (reference peak); m / z = 326 [M-CH ₃ ] ⁺ .

  c) 5-Chloro-3-ethynylpyridin-2-ylamine can be prepared by the following method.

  A suspension of 1.6 g of 5-chloro-3trimethylsilanylethynylpyridin-2-ylamine and 1.24 g of potassium fluoride in methanol (80 mL) is refluxed for about 3 hours 30 minutes. After returning to a temperature close to 20 ° C., the mixture is filtered through Celite, and the insoluble material is washed 3 times with 50 mL of methanol. The filtrate is concentrated to dryness under reduced pressure (13 kPa). The residue is taken up with 100 ml of methylene chloride. The resulting solution is washed 3 times with 60 mL of water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (13 kPa). 0.97 g of 5-chloro-3-ethynylpyridin-2-ylamine is thus obtained in solid form, the properties of which are as follows:

Silica TLC [eluent: cyclohexane / ethyl acetate (50/50 volume ratio)]
Rf = 0.72.

Mass spectrum (CI): m / z = 153 [M + H] ⁺ (reference peak).

  d) 5-Chloro-3-trimethylsilanylethynylpyridin-2-ylamine can be produced by the following method.

  A suspension of 2.54 g of 5-chloro-3-iodopyridin-2-ylamine, 2.12 mL of ethynyltrimethylsilane, 0.38 g of copper iodide and 0.47 g of lithium chloride in triethylamine (7 mL) and dimethylformamide (75 mL) Degas for about 15 minutes under argon. 0.408 g of [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) chloride is added to the above suspension. The mixture is heated at approximately 40 ° C. for approximately 19 hours and concentrated to dryness under reduced pressure (13 kPa). The residue is taken up with 50 mL of water and extracted three times with 100 mL of ethyl acetate. The combined organic phases are dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (13 kPa). The residue is purified by flash chromatography on a silica column [eluent: cyclohexane / ethyl acetate (70/30 volume ratio)]. 1.63 g of 5-chloro-3-trimethylsilanylethynylpyridin-2-ylamine is obtained in the form of a solid, the properties of which are as follows:

  Melting point: 108 ° C. (Kefler stand).

Mass spectrum (CI): m / z = 225 [M + H] ⁺ (reference peak).

  e) 5-Chloro-3-iodopyridin-2-ylamine can be prepared by the following method.

  A mixture of 6.43 g of 5-chloropyridin-2-ylamine and 12.38 g of N-iodosuccinimide in glacial acetic acid (300 mL) is heated at approximately 55 ° C. for 6 hours. After returning to a temperature of about 20 ° C., the mixture is stirred for about 18 hours and concentrated to dryness under reduced pressure (13 kPa). The residue is taken up with 400 mL of water and the pH of the resulting suspension is returned to about 8 by adding saturated aqueous sodium bicarbonate solution. The precipitate is filter dried, washed with water and vacuum dried at 40 ° C. for about 3 hours (13 kPa). 12.35 g of 5-chloro-3-iodopyridin-2-ylamine are obtained in the form of a solid, the properties of which are as follows:

Silica TLC [eluent: cyclohexane / ethyl acetate (50/50 volume ratio)]
Rf = 0.68.

Mass spectrum (EI): m / z = 254 [M] ⁺ (reference peak); m / z = 127 [M−I] ⁺ ; m / z = 100 [127−HCN] ⁺ ; m / z = 92 [ 127-Cl] ⁺ .

  f) 3-Iodo-5,6-dimethoxy-1-methyl-1H-indole can be produced by the following method.

  0.465 g of powdered potassium hydroxide is added to a solution of 0.5 g of 5,6-dimethoxy-1H-indole in dimethylformamide (15 mL). A solution of 0.725 g of iodine sublimated twice in dimethylformamide (15 mL) is added dropwise to the above mixture. The reaction medium is stirred for about 3 hours at a temperature in the region of 20 ° C., and then 0.21 mL of methyl iodide is added dropwise while maintaining the mixture at this same temperature by cooling with a water bath. After stirring at approximately 20 ° C. for 1 hour 30 minutes, the mixture is added to a solution of 1.5 g of sodium thiosulfate in water (150 mL) cooled to approximately 5 ° C. and stirred for approximately 10 minutes. The precipitate is filter dried, washed 5 times with 5 mL of water cooled to approximately 5 ° C. and vacuum dried (13 kPa) over phosphorus pentoxide. 0.78 g of 3-iodo-5,6-dimethoxy-1-methyl-1H-indole is obtained in the form of a solid, the properties of which are as follows:

  Melting point: 80-90 ° C. (decomposition) (Kefler stand).

Mass spectrum (EI): m / z = 317 [M] ⁺ (reference peak); m / z = 302 [M−CH ₃ ] ⁺ ; m / z = 190 [M−I] ⁺ .

(Example 104)
2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -5-fluoro-1H-pyrrolo [2,3-b] pyridine a) 3- (5,6-dimethoxy-1- Example 103a except that 0.19 g of methyl-1H-indol-3-ylethynyl) -5-fluoropyridin-2-ylamine and 0.263 g of potassium tert-butoxide are used in a solution of 1-methylpyrrolidin-2-one (15 mL) 2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -5-fluoro-1H-pyrrolo [2,3-b] pyridine can be produced in the same manner as in the above. . After flash chromatography on a silica column [eluent: methylene chloride / ethyl acetate (90/10 volume ratio)], 2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -5- 0.046 g of fluoro-1H-pyrrolo [2,3-b] pyridine is thus obtained in solid form, the properties of which are as follows:

  Melting point: 283 ° C. (Bucchi capillary).

¹ H NMR spectrum (300 MHz, (CD ₃ ) _2SO d6, δ ppm value): 3.83 (s: 3H); 3.87 (s: 3H); 3.89 (s: 3H); 6.76 (wide) 7.13 (s: 1H); 7.41 (s: 1H); 7.70 (dd, J = 9.5 and 3 Hz: 1H); 7.80 (s: 1H); 8 .06 (dd, J = 3 and 2.5 Hz: 1H); 11.87 (undivided peak: 1H). Mass spectrum (EI): m / z = 325 [M] ⁺ (reference peak); m / z = 310 [M-CH ₃ ] ⁺ ; m / z = 282 [M-CO] ⁺ .

  b) 3- (5,6-Dimethoxy-1-methyl-1H-indol-3-ylethynyl) -5-fluoropyridin-2-ylamine can be prepared by the following method.

  0.07 g of bis (triphenylphosphine) palladium (II) chloride was degassed with argon for about 15 minutes, 0.57 g of 3-ethynyl-5,6-dimethoxy-1-methyl-1H-indole, 5-fluoro-3 -Add to a suspension of 0.316 g iodopyridin-2-ylamine and 0.06 g copper iodide in triethylamine (39.5 mL) and dimethylformamide (20 mL) and stir the mixture at a temperature around 20 ° C for 18 hours and Concentrate down (13 kPa) to dryness. The residue is taken up with 150 mL of methylene chloride. The organic solution is washed 5 times with 50 mL of water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (13 kPa). The residue is purified by flash chromatography on a silica column [eluent: cyclohexane / ethyl acetate (50/50 volume ratio)]. 0.14 g of 3- (5,6-dimethoxy-1-methyl-1H-indol-3-ylethynyl) -5-fluoropyridin-2-ylamine is obtained in the form of a solid, the properties of which are as follows: .

  Silica TLC [eluent: methylene chloride / methanol (98/2 volume ratio)] Rf = 0.28.

Mass spectrum (CI): m / z = 326 [M + H] ⁺ (reference peak).

  c) In the same manner as in Example 103e, except that 5 g of 5-fluoropyridin-2-ylamine and 11.04 g of N-iodosuccinimide in glacial acetic acid (250 mL) were used, 5-fluoro-3-iodopyridine- 2-ylamine can be produced. This gives 6.1 g of 5-fluoro-3-iodopyridin-2-ylamine in solid form, the properties of which are as follows:

  Melting point: 70 ° C. (Kefler stand).

Mass spectrum (CI): m / z = 239 [M + H] ⁺ (reference peak).

  d) As in Example 103c, except that a solution of 1.71 g of 5,6-dimethoxy-1-methyl-3-trimethylsilanylethynyl-1H-indole and 1.04 g of potassium fluoride in methanol (70 mL) was used. Thus, 3-ethynyl-5,6-dimethoxy-1-methyl-1H-indole can be produced. 1 g of 3-ethynyl-5,6-dimethoxy-1-methyl-1H-indole is thus obtained in solid form, the properties of which are as follows:

  Silica TLC (eluent: methylene chloride) Rf = 0.49.

Mass spectrum (EI): m / z = 215 [M] ⁺ (reference peak); m / z = 200 [M−CH ₃ ] ⁺
m / z = 172 [M-CO] ^<+> .

  e) 5,6-Dimethoxy-1-methyl-3-trimethylsilanylethynyl-1H-indole can be produced by the following method.

  2.81 g of 3-iodo-5,6-dimethoxy-1-methyl-1H-indole obtained by degassing 0.421 g of bis (triphenylphosphine) palladium (II) chloride under argon for 15 minutes, ethynyltrimethylsilane Add to a suspension of 36 g and 0.457 g of copper iodide in triethylamine (150 mL). The mixture is stirred at a temperature around 20 ° C. for about 18 hours and heated at about 50 ° C. for about 24 hours. After returning to a temperature close to 20 ° C., the mixture is diluted with 100 mL of ethyl acetate and washed with 150 mL of water. The aqueous phase is back extracted twice with 150 mL ethyl acetate and the combined organic phases are washed with 200 mL saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (13 kPa). After filtration on silica and elution with methylene chloride, 1.71 g of 5,6-dimethoxy-1-methyl-3-trimethylsilanylethynyl-1H-indole is obtained in solid form, the properties of which are as follows: It is.

  Melting point: 124 ° C. (Kefler stand).

Mass spectrum (EI): m / z = 287 [M] ⁺ (reference peak); m / z = 272 [M−CH ₃ ] ⁺
m / z = 214 [M-SiMe ₃ ] ⁺ .

  3-Iodo-5,6-dimethoxy-1-methyl-1H-indole is described in Example 103f.

(Example 105)
2- [5,6-dimethoxy-1- (2-morpholin-4-ylethyl) -1H-indol-3-yl] -5-fluoro-1H-pyrrolo [2,3-b] pyridine a) 2- [ 5,6-Dimethoxy-1- (2-morpholin-4-ylethyl) -1H-indol-3-yl] -5-fluoro-1H-pyrrolo [2,3-b] pyridine is prepared by the following method. be able to.

  A solution of 2.08 g of potassium hydroxide in water (7 mL) was refluxed with 2- [5,6-dimethoxy-1- (2-morpholin-4-ylethyl) -1H-indol-3-yl] -5-fluoro. -1- (Toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine is added to a solution of 0.83 g of methanol (100 mL). The mixture is stirred at reflux for 3 hours 30 minutes. After returning to approximately 20 ° C., the mixture is concentrated to dryness under reduced pressure (13 kPa). The residue is taken up with 50 mL of water and extracted three times with 80 mL of methylene chloride. The combined organic phases are dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (13 kPa). The residue is purified by flash chromatography on a silica column [eluent: ethyl acetate / methanol (90/10 volume ratio)]. 0.37 g of 2- [5,6-dimethoxy-1- (2-morpholin-4-ylethyl) -1H-indol-3-yl] -5-fluoro-1H-pyrrolo [2,3-b] pyridine was solid. The following characteristics are obtained.

  Melting point: 205-210 ° C. (Kefler stand).

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value): 2.49 (wide t, J = 4.5 Hz: 4H); 2.73 (t, J = 6.5 Hz: 2H); 3.61 (wide t, J = 4.5 Hz: 4H); 3.87 (s: 3H); 3.89 (s: 3H); 4.32 (wide t, J = 6.5 Hz: 2H); 6.78 (wide s: 1H); 7.20 (s: 1H); 7.41 (s: 1H); 7.70 (dd, J = 9.5 and 3 Hz: 1H); 7.89 (s : 1H); 8.07 (dd, J = 3 and 2.5 Hz: 1H); 11.88 (undivided peak: 1H).

Mass spectrum (EI): m / z = 424 [M] ⁺ ; m / z = 100 [C ₅ H ₁₀ NO] ⁺ (reference peak).

  b) 5-Fluoro-2- [1- (2-iodoethyl) -5,6-dimethoxy-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3- b] 2- [5,6-dimethoxy-1- (2-morpholine) as in Example 100b except that 1 g of pyridine, 0.223 g of potassium carbonate and 0.28 mL of morpholine in acetonitrile (100 mL) were used. -4-ylethyl) -1H-indol-3-yl] -5-fluoro-1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine can be prepared. 2- [5,6-Dimethoxy-1- (2-morpholin-4-ylethyl) -1H-indol-3-yl] -5-fluoro-1- (toluene-4-sulfonyl) -1H-pyrrolo [2, 3-b] pyridine 0.83 g is thus obtained in solid form, the properties of which are as follows:

  Melting point: 182 ° C. (Kefler stand).

Mass spectrum (CI): m / z = 620 [M ′ + H) ⁺ ; m / z = 579 [M + H) ⁺ (reference peak).

  c) 5-Fluoro-2- [1- (2-chloroethyl) -5,6-dimethoxy-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3- b] 5-Fluoro-2- [1- (2-iodoethyl) -5, in the same manner as in Example 100c, except that a solution of 2 g of pyridine and 0.85 g of sodium iodide in 2-butanone (100 mL) was used. 6-Dimethoxy-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine can be prepared. Thus, 5-fluoro-2- [1- (2-iodoethyl) -5,6-dimethoxy-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3 -B] 2.2 g of pyridine are obtained in the form of a solid, the properties of which are as follows:

  Melting point: 176 ° C. (Kefler stage).

Mass spectrum (EI): m / z = 619 [M] ⁺ ; m / z = 492 [M−I] ⁺ ; m / z = 464 [M−C ₇ H ₇ O ₂ S] ⁺ (reference peak); m / z = 337 [464-I] ⁺ .

  d) 2 g of 2- (5,6-dimethoxy-1H-indol-3-yl) -5-fluoro-1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine, tetrabromide 5-Fluoro-2- [1 as in Example 100d except that a solution of 0.028 g of butylammonium, 1.89 g of potassium hydroxide and 1.38 g of potassium carbonate in 1,2-dichloroethane (50 mL) was used. -(2-Chloroethyl) -5,6-dimethoxy-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine can be prepared. After flash chromatography on a silica column [eluent: methylene chloride / methanol (98.5 / 1.5 volume ratio)], 5-fluoro-2- [1- (2-chloroethyl) -5,6-dimethoxy- 1H-Indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine 2.05 g is thus obtained in solid form, which has the following properties Street.

  Melting point: 150 ° C. (Kefler stage).

Mass spectrum (EI): m / z = 527 [M] ⁺ ; m / z = 372 [M−C ₇ H ₇ O ₂ S] ⁺ (reference peak).

  e) 2- (5,6-Dimethoxy-1H-indol-3-yl) -5-fluoro-1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine is prepared by the following method. Can be manufactured.

  3.1 g of 5-fluoro-2-iodo-1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine, 1-tert-butyloxycarbonyl-5,6-dimethoxy-1H-indole A mixture of 2.4 g of -3-boronic acid and 20.3 mL of saturated aqueous sodium bicarbonate in dimethylformamide (100 mL) is degassed with argon for about 15 minutes and 0.43 g of tetrakis (triphenylphosphine) palladium is added. The mixture is heated at about 110 ° C. for about 2 hours and concentrated to dryness under reduced pressure (13 kPa). The residue is taken up with 500 mL of water and extracted three times with 250 mL of ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The residue is taken up with 100 ml of diisopropyl ether, dried with a filter, washed 3 times with 20 ml of diisopropyl ether and vacuum dried (13 kPa) in the presence of potassium hydroxide chips at a temperature close to 20 ° C. 2.66 g of 2- (5,6-dimethoxy-1H-indol-3-yl) -5-fluoro-1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine is in solid form And its characteristics are as follows.

  Melting point: 218 ° C. (Kefler stand).

Mass spectrum (EI): m / z = 465 [M] ⁺ ; m / z = 310 [M−C ₇ H ₇ O ₂ S] ⁺ (reference peak).

  1-tert-Butyloxycarbonyl-5,6-dimethoxy-1H-indole-3-boronic acid is prepared according to the method described in patent WO03000688A1.

  f) 5-Fluoro-2-iodo-1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine can be produced by the following method.

  A solution of 3.5 g of 5-fluoro-1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine in tetrahydrofuran (100 mL) was cooled to about −78 ° C. Is maintained at around -75 ° C, and 7.54 mL of a 1.6N hexane solution of n-butyllithium is added dropwise. After stirring at the same temperature for about 1 hour, a solution of 6.12 g of iodine sublimated twice in tetrahydrofuran (50 mL) is added dropwise. After returning the temperature to approximately 20 ° C., the reaction mixture is diluted with 600 mL of ethyl acetate, washed 3 times with 100 mL of 5% aqueous sodium thiosulfate solution, dehydrated with magnesium sulfate, treated with vegetable charcoal, filtered, and reduced pressure Concentrate down (13 kPa) to dryness. The residue is taken up with 30 ml of diisopropyl ether, filtered through a filter, washed 3 times with 5 ml of diisopropyl ether and dried in vacuo (13 kPa). 3.6 g of 5-fluoro-2-iodo-1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine are obtained in the form of a solid, the properties of which are as follows:

  Melting point: 158 ° C. (Kefler stand).

Mass spectrum (EI): m / z = 416 [M] ⁺ ; m / z = 352 [M—SO ₂ ] ⁺ ; m / z = 155 [C ₇ H ₇ O ₂ S] ⁺ ; m / z = 91 [C ₇ H ₇ ] ⁺ (reference peak).

  g) 5-Fluoro-1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine can be produced by the following method.

  2.3 g of 5-fluoro-1H-pyrrolo [2,3-b] pyridine, 3.54 g of 4-methylbenzenesulfonyl chloride, 7.56 g of sodium hydroxide dissolved in 55 mL of water and 0.115 g of tetrabutylammonium hydrogen sulfate The mixture in toluene (125 mL) is stirred at approximately 20 ° C. for about 24 hours. The mixture is diluted with 500 mL of ethyl acetate and the organic phase is washed 3 times with 200 mL of water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (13 kPa). The residue is purified by flash chromatography on a silica column [eluent: methylene chloride]. 3.85 g of 5-fluoro-1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine are obtained in the form of a solid, the properties of which are as follows:

  Melting point: 160 ° C. (Kefler stand).

Mass spectrum (EI): m / z = 290 [M] ⁺ ; m / z = 226 [M-SO ₂ ] ⁺ ; m / z = 155 [C ₇ H ₇ O ₂ S] ⁺ ; m / z = 91 [C ₇ H ₇ ] ⁺ (reference peak).

  h) 5-Fluoro-1H-pyrrolo [2,3-b] pyridine can be prepared by the following method.

  About 4 hours elapsed with a mixture of 3.8 g of 5-fluoro-3-trimethyl-silanylethynylpyridin-2-ylamine and 3.4 g of potassium tert-butoxide in 1-methylpyrrolidin-2-one (100 mL) at approximately 130 ° C. Let After returning to a temperature close to 20 ° C., the mixture is placed in 1000 mL of saturated aqueous sodium chloride solution and extracted five times with 250 mL of diethyl ether. The organic phases are combined, washed 5 times with 100 mL of saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (13 kPa). 2.35 g of 5-fluoro-1H-pyrrolo [2,3-b] pyridine is obtained in the form of a solid, the properties of which are as follows:

  Melting point: 110 ° C. (Kefler stand).

Mass spectrum (EI): m / z = 136 [M] ⁺ (reference peak); m / z = 109 [M-HCN] ⁺ .

  i) 14 g of 5-fluoro-3-iodopyridin-2-ylamine, 12.47 mL of ethynyltrimethylsilane, 2.24 g of copper iodide, 2.74 g of lithium chloride, 41.33 mL of triethylamine and [1,1′bis (diphenylphosphine) [Fino) ferrocene] palladium (II) chloride Prepare 5-fluoro-3-trimethylsilanylethynylpyridin-2-ylamine according to the method described in Example 103d except that 2.15 g of dimethylformamide (441 mL) solution is used. be able to. After flash chromatography on a silica column (eluent: methylene chloride), 7.91 g of 5-fluoro-3-trimethylsilanylethynylpyridin-2-ylamine is thus obtained in solid form, which has the following characteristics: It is as follows.

  Melting point: 65 ° C. (Kefler stand).

Mass spectrum (EI): m / z = 208 [M] ⁺ ; m / z = 193 [M−CH ₃ ] ⁺ (reference peak).

  5-Fluoro-3-iodopyridin-2-ylamine is described in Example 104c.

(Example 106)
2- {5,6-dimethoxy-1- [2- (4-methylpiperazin-1-yl) ethyl] -1H-indol-3-yl} -5-fluoro-1H-pyrrolo [2,3-b] -Pyridine a) 2- {5,6-dimethoxy-1- [2- (4-methylpiperazin-1-yl) ethyl] -1H-indol-3-yl} -5-fluoro-1- (toluene-4 -Sulfonyl) -1H-pyrrolo [2,3-b] pyridine as in Example 105a, except that 0.82 g of pyridine dissolved in 100 mL of methanol and 2 g of potassium hydroxide dissolved in 7 mL of water were used. , 2- {5,6-dimethoxy-1- [2- (4-methylpiperazin-1-yl) ethyl] -1H-indol-3-yl} -5-fluoro-1H-pyrrolo [2,3-b ] To produce pyridine Door can be. After flash chromatography on a silica column [eluent: methylene chloride / methanol (70/30 volume ratio)], 2- {5,6-dimethoxy-1- [2- (4-methyl-piperazin-1-yl) 0.37 g of ethyl] -1H-indol-3-yl} -5-fluoro-1H-pyrrolo [2,3-b] pyridine is thus obtained in solid form, the properties of which are as follows: .

  Melting point: 210 ° C. (Kefler stand).

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value) 2.16 (s: 3H); 2.32 (undivided peak: 4H); 2.40 to 2.55 (mt: 4H) 2.73 (wide t, J = 6.5 Hz: 2H); 3.87 (s: 3H); 3.89 (s: 3H); 4.30 (wide t, J = 6.5 Hz: 2H); 6.76 (wide s: 1H); 7.18 (s: 1H); 7.42 (s: 1H); 7.71 (dd, J = 9.5 and 3 Hz: 1H); 7.88 ( s: 1H); 8.07 (mt: 1H); 11.87 (unresolved peak: 1H).

Mass spectrum (EI): m / z = 437 [M] ⁺ ; m / z = 113 [C ₆ H ₁₃ N ₂ ] ⁺ (reference peak); m / z = 70 [C ₄ H ₈ N] ⁺ .

  b) 5-Fluoro-2- [1- (2-iodoethyl) -5,6-dimethoxy-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3- b] 2- [5,6-dimethoxy-1- [2] according to the method described in Example 100b, except that a solution of 1 g of pyridine, 0.223 g of potassium carbonate and 0.323 g of 1-methylpiperazine in acetonitrile (100 mL) was used. Preparation of-(4-methylpiperazin-1-yl) ethyl] -1H-indol-3-yl] -5-fluoro-1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine can do. 2- [5,6-Dimethoxy-1- [2- (4-methylpiperazin-1-yl) ethyl] -1H-indol-3-yl] -5-fluoro-1- (toluene-4-sulfonyl)- 0.83 g of 1H-pyrrolo [2,3-b] pyridine is thus obtained in solid form, the properties of which are as follows:

  Melting point: 188 ° C. (Kefler stand).

Mass spectrum (EI): m / z = 591 [M] ⁺ ; m / z = 491 [M−C ₄ H ₈ N] ⁺ ; m / z = 436 [M−C ₇ H ₇ O ₂ S] ⁺ ; m / z = 113 [C ₆ H ₁₃ N ₂ ] ⁺ (reference peak); m / z = 70 [C ₄ H ₈ N] ⁺ .

(Example 107)
[1-carboxymethyl-5-methoxy-3- (1H-pyrrolo- [2,3-b] pyridin-2-yl) -1H-indol-6-yloxy] acetic acid a) [1-carboxymethyl-5- Methoxy-3- (1H-pyrrolo [2,3-b] -pyridin-2-yl) -1H-indol-6-yloxy] acetic acid is prepared by the following method.

  0.3 mL of methanolic potassium hydroxide solution (0.1 g / mL) was added to {5-methoxy-1-methoxycarbonylmethyl-3- [1- (toluene-4sulfonyl) -1H-pyrrolo [2,3-b]. ] Pyridin-2-yl] -1H-indol-6-yloxy} acetic acid ester (0.056 g; 97.1 μmol) is placed in a lysis vessel and the mixture is stirred at 20 ° C. for 16 hours. Reverse phase liquid chromatography mass spectrometry shows that the expected product is formed but not the major component. The purification efforts at this stage of the reaction were unsuccessful and none of the obtained compounds, including a mixture of raw materials and expected product, were evaporated, and again with 2 mL of methanolic potassium hydroxide (0.1 g / mL) over 20 hours. React. The reaction mixture becomes a milky color. The mixture is evaporated to dryness and taken up in a mixture of 1 mL dimethyl sulfoxide and 1 mL 6M aqueous hydrochloric acid. The solution thus obtained is purified by reverse phase liquid chromatography mass spectrometry (Method C) after filtering off the white precipitate that has formed. After evaporation of the fractions, the tubes containing the expected compound were combined and [1-carboxymethyl-5-methoxy-3- (1H-pyrrolo [2,3-b] pyridin-2-yl) -1H-indole. -6-yloxy] acetic acid (0.015 g; 31%) is obtained, the properties of which are as follows:

LC / MS analysis: tr = 2.9 min [M + H] ⁺ ; m / z = 396.17 [M + H] ⁺ .

  b) {5-Methoxy-1-methoxycarbonylmethyl-3- [1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridin-2-yl] -1H-indol-6-yloxy } The methyl ester of acetic acid is prepared by the following method.

  Dimethyl 5-methoxy-3- [1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridin-2-yl] -1H-indol-6-ol (0.043 g; 100 μmol) A formamide (10 mL) solution is placed in a 1.3 × 10 cm lysate, potassium carbonate (0.027 g; 200 μmol) is added, and the mixture is stirred at room temperature for 5 minutes. Methyl bromoacetate (0.028 mL; 300 μmol) was added and the mixture was heated at 50 ° C. for 4 hours. TLC management (eluent: 50/50 volume ratio cyclohexane / ethyl acetate) showed that the reaction was complete. It is. The reaction mixture is taken up in 5 mL of distilled water and the reaction mixture is extracted with ethyl acetate (15 mL). The combined extracts were washed with water (20 mL), dried over magnesium sulfate, filtered and evaporated to give the crude compound which was purified by chromatography on silica gel, eluting with cyclohexane and ethyl acetate. (60/40 volume ratio). Fractions containing the expected compound were combined and evaporated to give {5-methoxy-1-methoxycarbonylmethyl-3- [1- (toluene-4sulfonyl) -1H-pyrrolo [2,3-b] pyridine- 2-Iyl] -1H-indol-6-yloxy} acetic acid methyl ester (0.056 g; 97%) was obtained, the properties of which are as follows:

LC / MS analysis: tr = 4.1, m / z = 578.1 [M + H] ⁺ .

  c) 5-methoxy-3- [1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridin-2-yl] -1H-indol-6-ol is prepared by the following method. To do.

  In a 100 mL 3-neck flask, 2- (6-benzyloxy-5-methoxy-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine ( A solution of 0.52 g; 993 μmol) in acetonitrile (40 mL) is treated with trimethylsilyl iodide (0.353 mL; 2.483 mmol; 2.5 equivalents) at 50 ° C. for 2 hours and then at 20 ° C. for 16 hours. . After evaporation, the reaction mixture is taken up in a mixture of methylene chloride (50 mL) and water (50 mL) and separated by settling. The aqueous phase was extracted with methylene chloride (250 mL), the extracts were combined, dried over magnesium sulfate and evaporated to give the compound, which was purified by chromatography on silica gel (10 g, 35 μm silica), Elution is performed with a mixture of cyclohexane and ethyl acetate (60/40 volume ratio). Fractions containing the expected compound were combined and evaporated to give a solid that was triturated in diisopropyl ether to give 5-methoxy-3- [1- (toluene-4-sulfonyl) -1H-pyrrolo. [2,3-b] pyridin-2-yl] -1H-indol-6-ol, (0.215 g; 50%) was obtained, the properties of which are as follows:

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value): 2.30 (s: 3H); 3.75 (s: 3H); 6.75 (s: 1H); 6.90 ( 6.93 (wide s: 1H); 7.26 (wide d, J = 8.5 Hz: 2H); 7.304 (dd, J = 8 and 5 Hz: 1H); 7.42 ( d, J = 2.5 Hz: 1H); 7.57 (wide d, J = 8.5 Hz: 2H); 7.94 (dd, J = 8 and 1.5 Hz: 1H); 8.34 (dd, J = 5 and 1.5 Hz: 1H); 8.71 (wide s: 1H); 11.08 (wide s, 1H).

(Example 108)
{5-Methoxy-1-methyl-3- [1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridin-2-yl] -1H-indol-6-yloxy} acetic acid a) {5-Methoxy-1-methyl-3- [1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridin-2-yl] -1H-indol-6-yloxy} acetic acid, It is manufactured by the following method.

  {5-Methoxy-1-methyl-3- [1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridin-2-yl] -1H-indol-6-yloxy} methyl acetate ( 0.91 g; 1.751 mmol) in methanolic potassium hydroxide (74 mL, 1 g / mL) is placed in a 100 mL round bottom flask and stirred at 20 ° C. for 16 hours. After the reaction, the formed precipitate is filtered off and washed with methanol (20 mL). The solid water (30 mL) suspension is placed in a 250 mL Erlenmeyer flask and the pH is adjusted to 4 with 2N aqueous hydrochloric acid. The resulting yellow solid is triturated in the reaction mixture, filtered, washed with water and dried in vacuo. {5-Methoxy-1-methyl-3- [1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridin-2-yl] -1H-indol-6-yloxy} acetic acid (0 666 g; 98%) is isolated and its properties are as follows:

Mass spectrum (IC): m / z = 352 [M + H] ⁺ (reference peak).

  b) {5-Methoxy-1-methyl-3- [1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridin-2-yl] -1H-indol-6-yloxy} acetic acid Is prepared by the following method.

  5-methoxy-1-methyl-3- [1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridin-2-yl] -1H-indol-6-ol, (0.558 g A solution of 1.247 mmol) in dimethylformamide (10 mL) is placed in a 25 mL 3-neck flask under argon, sodium hydride (0.045 g; 1.49 mmol) is added and the mixture is stirred at room temperature for 10 minutes. As soon as no more gas was evolved, methyl bromoacetate (0.142 mL; 1.496 mmol) was added dropwise and the mixture was allowed to stand at room temperature for 3 hours with stirring. The reaction mixture is taken up in 100 mL of distilled water and the resulting solid is filtered and washed with water (30 mL). The solid is dissolved in methylene chloride (150 mL) and the solution thus obtained is washed with distilled water (50 mL), dried over magnesium sulfate and evaporated under reduced pressure to give {5-methoxy-1-methyl. Methyl-3- [1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridin-2-yl] -1H-indol-6-yloxy} acetate is obtained in the form of a brown oil. (0.5 g; 77%), the characteristics are as follows.

LC / MS analysis: tr = 4.1 min; m / z = 520.13 [M + H ⁺ ).

  c) 5-Methoxy-1-methyl-3- [1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridin-2-yl] -1H-indol-6-ol It is manufactured by the method.

  2- (6-Benzyloxy-5-methoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine (1.5 g 2.79 mmol) in acetonitrile (120 mL) is placed in a 250 mL 3-neck flask at 20 ° C. and trimethylsilyl iodide (0.956 mL; 6.97 mmol) is added dropwise. The reaction mixture is heated at 50 ° C. for 4 hours and evaporated to dryness under reduced pressure. The solvent residue is taken up in methylene chloride (200 mL) and washed with distilled water (1 × 200 mL). The extracts were combined, washed with distilled water, dehydrated with magnesium sulfate and evaporated under reduced pressure to give the crude compound which was chromatographed on a silica cartridge (AIT FlashSmart Pack, BP -61010300-093, 50 g silica), elution is carried out in a methylene chloride / ethyl acetate (95/5 volume ratio) mixture at 15 mL / min. Fractions containing the expected product were combined and evaporated to give 5-methoxy-1-methyl-3- [1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine-2. -Il] -1H-indol-6-ol (0.87 g; 70%) is obtained in the form of an ocher foam which is used as such in the next step.

  d) 2- (6-Benzyloxy-5-methoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine, It is manufactured by the following method.

  2- (6-Benzyloxy-5-methoxy-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine (1 g, 1.9 mmol) The dimethylformamide (10 mL) solution is placed in a 25 mL 3 neck flask under argon, sodium hydride (0.063 g; 2.101 mmol) is added and the mixture is stirred for 15 minutes. When no more gas is generated, methyl iodide (0.131 mL, 2.101 mmol) is added dropwise and the mixture is allowed to react at 21 ° C. for 2 hours. The reaction medium is taken up in 100 ml of distilled water and extracted twice with 100 ml of methylene chloride. The organic extracts are combined, dried over magnesium sulfate, filtered, and evaporated to dryness under reduced pressure. The evaporated compound is triturated in diisopropyl ether. The powdered solid compound thus obtained is filtered off and washed. 2- (6-Benzyloxy-5-methoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] -pyridine (0. 888 g (86%) are isolated in the form of a beige solid, the properties of which are as follows:

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value): 2.30 (s: 3H); 3.77 (s: 3H); 3.87 (s: 3H); 5.21 ( 6.76 (s: 1H); 7.00 (s: 1H); 7.27 (wide d, J = 8.5 Hz: 2H); 7.29 (s: 1H); 31 (dd, J = 8 and 5 Hz: 1H); 7.39 (wide t, J = 7.5 Hz: 1H); 7.47 (wide t, J = 7.5 Hz: 2H); 7.51 (s : 1H); 7.55 to 7.65 (mt: 4H); 7.95 (dd, J = 8 and 1.5 Hz: 1H); 8.36 (dd, J = 5 and 1.5 Hz: 1H) .

  2- (6-Benzyloxy-5-methoxy-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine is prepared by the method described in Patent WO03000688A1. Manufactured according to

(Examples 109 to 146)
Preparation of Reagent [5-Methoxy-1-methyl-3- (1H-pyrrolo [2,3-b] -pyridin-2-yl) -1H-indol-6-yloxy] acetic acid (prepared by the method of Example 108) ) (0.228 g; 0.585 mmol) in dimethylformamide (3.25 mL; solution A) and N, N′-dicyclohexylcarbodiimide (0.465 g, 2.25 mmol) in dimethylformamide (3.75 mL; solution C) ) And 1-hydroxybenzotriazole (0.206 g; 1.52 mmol) and dimethylaminopyridine (0.015 g; 0.12 mmol) in dimethylformamide (3.75 mL; solution D) are prepared and placed in a container.

  Each amine in the table below can be weighed and diluted with dimethylformamide.

Table 1: Reagents used

Production of non-commercial amines used
Preparation of cis-perhydropyrrolo [3,4-c] pyrrole-1,3-dione (Example 118) a) Preparation of cis-perhydropyrrolo [3,4-c] pyrrole-1,3-dione by the following method To do.

  A solution of 5-benzyl-tetrahydropyrrolo [3,4-c] -pyrrole-1,3-dione (11.5 g; 49.9 mmol) in ethanol (200 mL) was placed in a 1000 mL autoclave and palladium / activated carbon (5%; 2 g; 0.9 mmol). After purging the reactor with nitrogen, the autoclave is placed under 5.8 MPa (58 bar) of hydrogen at 70 ° C. for 16 hours. After returning to 20 ° C. and filtering and washing of the catalyst, the solvent is distilled off under reduced pressure, and the resulting solid is recrystallized from methanol (100 mL) and vacuum dried to a constant weight. Perhydropyrrolo [3,4-c] pyrrole-1,3-dione (3.6 g) was isolated and its properties are as follows.

  Melting point: 222 ° C. (Kefler stand).

  b) 5-Benzyl-tetrahydro-pyrrolo [3,4-c] pyrrole-1,3-dione is prepared by the following method.

  An ethanol suspension of 2-acetyl-5-benzyltetrahydro-pyrrolo [3,4-c] pyrrole-1,3-dione (107.7 g; 395 mmol) was placed in a 1000 mL round bottom flask and the suspension was elevated. While warming, 4N aqueous sodium hydroxide solution (200 mL) is added simultaneously. The reaction mixture is stirred for 30 minutes and evaporated under reduced pressure. The evaporated residue is taken up in a mixture of water (100 mL) and ethyl acetate (300 mL) and acidified to pH 4 by adding 4N aqueous hydrochloric acid (100 mL). After separation by settling and extraction with ethyl acetate (2 x 200 mL), the organic extracts are combined, washed with brine (100 mL), dried over magnesium sulfate, filtered, and evaporated under reduced pressure. The solvent distilled residue is crystallized from ethanol (100 mL) and 7.5 g of the resulting solid is recrystallized from acetonitrile (25 mL). The resulting solid is filtered off, washed with acetonitrile (5 mL) and vacuum dried to a constant weight. 5-Benzyltetrahydro-pyrrolo [3,4-c] pyrrole-1,3-dione (5.8 g) was isolated and its properties are as follows.

  Melting point: 158 ° C. (Kefler stand).

  c) 2-acetyl-5-benzyltetrahydropyrrolo [3,4-c] pyrrole-1,3-dione is prepared by the following method.

A mixture of N-acetylmaleimide (64 g; 460 mmol) and n-butoxymethyl-n-trimethylsilylmethylbenzylamine (128 g; 460 mmol) in methylene chloride (1000 mL) was placed in a 2000 mL 3-neck flask and the reaction mixture was cooled to 10 ° C. And Add trifluoroacetic acid (0.5 cm ³ ) while maintaining effective stirring. The temperature of the reaction mixture is increased to 38 ° C. over 15 minutes. Potassium carbonate (100 g) is added and the reaction mixture is stirred at 20 ° C. for 48 hours. The solid is removed by filtration and the filtrate is evaporated under reduced pressure. The resulting oil is purified by chromatography on silica gel (silica, 40-63 μm, eluent: 65/35 volume ratio cyclohexane / ethyl acetate). Fractions containing the expected compound were combined and evaporated under reduced pressure to give 2-acetyl-5-benzyltetrahydropyrrolo [3,4-c] pyrrole-1,3-dione, (107.7 g; 86%) Is obtained in the form of a brown oil which is used directly in the next step.

  d) N-acetylmaleimide is produced by the following method.

  A solution of maleimide (68 g; 700 mmol) in acetic anhydride (500 mL) is placed in a 1000 mL 3-neck flask and the reaction mixture is refluxed for 3 hours. After returning to 20 ° C., the reaction mixture is evaporated under reduced pressure to give an oil which is crystallized from ethyl acetate (100 mL). After the solid was filtered, washed with ethyl acetate (25 mL) and diisopropyl ether (100 mL) and vacuum dried to constant weight, N-acetylmaleimide (64.1 g; 65.8%) was isolated and its properties Is as follows.

  Melting point: 58 ° C. (Kefler stand).

Preparation of cis-perhydropyrrolo [3,4-c] pyrrol-1-one (Example 128) a) Hexahydropyrrolo [3,4-c] pyrrol-1-one is prepared by the following method.

  A solution of 5-benzylhexahydropyrrolo [3,4-c] -pyrrol-1-one, (7.2 g; 33 mmol) in pure ethanol (100 mL) was placed in a 250 mL autoclave and 5% palladium / activated carbon (1. 5 g) is added. After purging with nitrogen, the autoclave is placed under 5.6 MPa (56 bar) of hydrogen at 70 ° C. for 16 hours. After returning to 20 ° C., the catalyst is filtered off and the filtrate is evaporated under reduced pressure. The resulting compound is taken up in refluxing acetonitrile (15 mL) and filtered through filter paper under hot conditions to crystallize. After crystallization, the resulting solid is filtered off, washed with acetonitrile (3 mL) and then with diethyl ether (20 mL) and finally vacuum dried to constant weight. Hexahydropyrrolo [3,4-c] pyrrol-1-one (1.3 g; 31%) was isolated and its properties are as follows.

  Melting point: 145 ° C. (Kefler stand).

  b) 5-Benzylhexahydropyrrolo [3,4-c] pyrrol-1-one is prepared by the following method.

  A suspension of 5-benzyl-3-hydroxyhexahydropyrrolo [3,4-c] pyrrol-1-one (7 g; 30 mmol) in methylene chloride (50 mL) is placed in a 1000 mL 3-neck flask and cooled in an ice bath. Trimethylsilane (7.1 g; 60 mmol) is added slowly at 3 ° C. The reaction mixture becomes homogeneous and it is reacted for 10 minutes at 25 ° C., cooled to 3 ° C. and added to trifluoroacetic acid (50 mL). The reaction mixture is stirred at 20 ° C. for 16 hours and evaporated under reduced pressure. The residue is taken up in a mixture of ethyl acetate (100 mL) and 4N aqueous sodium peroxide (50 mL), separated by settling and washed with water (100 mL). After drying over magnesium sulphate and evaporation under reduced pressure, a yellow oil is isolated and purified by chromatography on silica gel (silica: 40-63 μm, eluent: 90/10 ethyl acetate / methanol). . Fractions containing the expected compound were combined and evaporated under reduced pressure to give 5-benzylhexahydropyrrolo [3,4-c] pyrrol-1-one (7.2 g), which was the next step Use directly at.

  c) 5-Benzyl-3-hydroxyhexahydropyrrolo [3,4-c] pyrrol-1-one is prepared by the following method.

  5-Benzyltetrahydropyrrolo [3,4-c] -pyrrole-1,3-dione (12.7 g; 55 mmol) {cis-perhydropyrrolo [3,4-c] pyrrole-1,3-dione in a 500 mL 3 neck flask The solution of Preparation} described for preparation of (b) is added to a tetrahydrofuran suspension of lithium aluminum tetrahydride (2 g; 55 mmol) cooled to 3 ° C. in an ice bath. The reaction mixture is stirred at this temperature for 25 minutes and water (2 mL), 4N aqueous sodium hydroxide (2 mL) and water (6 mL) are added in that order. The solid so formed is removed by filtration and the filtrate is dried over magnesium sulfate and evaporated under reduced pressure to give a white solid that is triturated in diisopropyl ether (50 mL). The resulting solid is filtered off, washed with diisopropyl ether (25 mL) and vacuum dried to constant weight. 5-Benzyl-3-hydroxyhexahydropyrrolo [3,4-c] pyrrol-1-one (7 g; 55%) was isolated and its properties are as follows.

  Melting point: 138 ° C. (Kefler stand).

(Example 137)
Preparation of (3aR, 6aS) -2-phenyltetrahydro-pyrrolo [3,4-c] pyrrole-1,3-dione hydrochloride a) (3aR, 6aS) -2-phenyltetrahydropyrrolo [3,4-c] Pyrrole-1,3-dione hydrochloride is produced by the following method.

  A suspension of 2-phenyltetrahydropyrrolo [3,4-c] -pyrrole-1,3-dione (8 g; 37 mmol) in ethanol (80 mL) is placed in a 250 mL 3-neck flask and the reaction mixture is brought to 70 ° C. The solution thus obtained is treated with 4.9N hydrochloric acid ethanol solution (37 mmol) under hot conditions and returned to 20 ° C. The resulting solid is filtered off, washed with ethanol (10 mL) and then with diethyl ether (25 mL) and vacuum dried to constant weight. 2-Phenyltetrahydropyrrolo [3,4-c] pyrrole-1,3-dione hydrochloride (6.85 g; 73.1%) was isolated and its properties are as follows.

  Melting point: 250 ° C. (Kefler stand).

  b) 2-Phenyltetrahydropyrrolo [3,4-c] pyrrole-1,3-dione is produced by the following method.

  Pure ethanol (93.2 g; 304 mmol) of 5-benzyl-2-phenyltetrahydro-pyrrolo [3,4-c] pyrrole-1,3-dione (93.2 g; 304 mmol) from which hydrochloride was removed by pretreatment with 4N sodium hydroxide. 1200 mL) solution is placed in a 5000 mL autoclave and 5% palladium / activated carbon (11 g) is added. After purging with nitrogen, the autoclave is placed under 6.4 MPa (64 bar) of hydrogen at 70 ° C. for 12 hours. After returning to 20 ° C., the catalyst is filtered off and the filtrate is evaporated under reduced pressure. The resulting compound is triturated in diisopropyl ether (500 mL) and the resulting solid is filtered off, washed with diisopropyl ether and finally vacuum dried to constant weight. 2-Phenyltetrahydropyrrolo [3,4-c] pyrrole-1,3-dione, (6.6 g; 92%) was isolated and its properties are as follows.

  Melting point: 128 ° C. (Kefler stand).

  c) 5-Benzyl-2-phenyltetrahydropyrrolo [3,4-c] pyrrole-1,3-dione is prepared by the following method.

  A mixture of phenylmaleimide (77.85 g; 450 mmol) and n- (butoxymethyl) -n- (trimethylsilylmethyl) benzyl-amine (180 g; 450 mmol) in methylene chloride (1000 mL) was placed in a 2000 mL 3-neck flask and effectively Add trifluoroacetic acid (0.1 mL) while maintaining stirring. The temperature of the reaction mixture is raised during the 2 hour reaction to 36 ° C., potassium carbonate (100 g) is added and the reaction mixture is stirred at 20 ° C. for 15 minutes. The solid is removed by filtration and the filtrate is evaporated under reduced pressure. The oil obtained is dissolved in acetone (2000 mL), treated with 4.9N hydrochloric acid in ethanol (490 mmol) and stirred at 20 ° C. for 16 hours. The resulting solid is filtered off, washed with acetone (150 mL) and diethyl ether (250 mL) and dried in vacuo to a constant weight. 5-Benzyl-2-phenyltetrahydropyrrolo [3,4-c] pyrrole-1,3-dione hydrochloride (129 g) is isolated and used directly in the next step.

(Example 138)
Preparation of (3aR, 6aS) -2-benzyl-tetrahydropyrrolo [3,4-c] pyrrole-1,3-dione hydrochloride a) (3aR, 6aS) -2-benzyltetrahydropyrrolo [3,4-c] Pyrrole-1,3dione hydrochloride is produced by the following method.

  A solution of 2,5-dibenzyltetrahydropyrrolo- [3,4-c] pyrrole-1,3-dione (253 g; 790 mmol) in ethanol (2000 mL) was placed in a 5000 mL autoclave and 5% palladium / activated carbon (2 g; 0 .9 mmol) is added. After purging the reactor with nitrogen, the autoclave is placed under 5.9 MPa (59 bar) of hydrogen at 70 ° C. for 16 hours. After returning to 20 ° C., the catalyst is filtered off and washed, the reaction mixture is concentrated under reduced pressure to 2000 mL and an ethanol solution of 9.6N hydrochloric acid (90 mL) is added. The resulting crystallized solid is filtered off, washed with ethanol (100 mL) and diethyl ether (250 mL) and finally vacuum dried to constant weight. 2-Benzyltetrahydropyrrolo [3,4-c] pyrrole-1,3-dione hydrochloride (3.6 g) was isolated and its properties are as follows.

  Melting point: 240 ° C. (Kefler stand).

  b) 2,5-Dibenzyltetrahydropyrrolo [3,4-c] pyrrole-1,3-dione is prepared by the following method.

  A mixture of benzylmaleimide (70.4 g; 376 mmol) and n- (butoxymethyl) -n- (trimethylsilylmethyl) benzylamine (105 g; 376 mmol) in methylene chloride (1000 mL) was placed in a 2000 mL 3-neck flask and stirred effectively. While maintaining, add trifluoroacetic acid (1 mL). The temperature of the reaction mixture is raised to 33 ° C. over 1 hour reaction time, potassium carbonate (50 g) is added and the reaction mixture is stirred at 20 ° C. for 10 minutes. The solid is removed by filtration and the filtrate is evaporated under reduced pressure. The resulting oil is taken up in diisopropyl ether (500 mL) and triturated until crystallization occurs. The resulting solid is filtered off, washed with diisopropyl ether (50 mL) and vacuum dried to constant weight. 2,5-Dibenzyltetrahydropyrrolo [3,4-c] pyrrole-1,3-dione (70 g; 58%) was isolated and its properties are as follows.

  Melting point: 100 ° C. (Kefler stand).

  0.25 mL of solution A (50 μmol / reactor), 0.25 mL of solution B, each amine solution in the table above, 0.25 mL of solution C and 0.035 mL of triethylamine in that order in a set of reactors suitable for parallel synthesis. Distribute. The reactor is sealed, stirred and heated at 88 ° C. for 4 hours 30 minutes. After returning to room temperature, the reactor is stirred for 48 hours. The contents of each reactor are filtered and each filtrate is solid phase extraction cartridge (2 mmol SCX phase / cartridge at 0.8 mmol / g, pre-wet with methanol: 5 parts by volume; first eluent: 5 parts by volume Methanol) and desorbed with 5 parts by volume of methanol / ammonia (2M) as the second eluent. After evaporation of the ammoniacal methanol, the compound is diluted with 1 mL of dimethyl sulfoxide and purified by reverse phase liquid chromatography mass spectrometry (Method C). Fractions containing the expected compound are evaporated, weighed, diluted with dimethyl sulfoxide to 10 mM and analyzed by reverse phase liquid chromatography mass spectrometry.

  1. The purified compound is then characterized by retention time and molecular peak (table below).

  2. [5-Methoxy-1-methyl-3- (1H-pyrrolo [2,3-b] pyridin-2-yl) -1H-indol-6-yloxy] acetic acid (prepared by the method of Example 88) and the above table Further reverse phase liquid chromatography mass spectrometry (Method D) cycles are performed on compounds derived from coupling of the precursors mentioned in columns 16, 17, 18 and 19. Fractions containing the expected compound are evaporated, weighed, diluted with dimethyl sulfoxide to 10 mM and analyzed by reverse phase liquid chromatography mass spectrometry. The purified compound is characterized by retention time and molecular peak (table below).

  3. [5-Methoxy-1-methyl-3- (1H-pyrrolo [2,3-b] pyridin-2-yl) -1H-indol-6-yloxy] acetic acid and 21, 22, 23, 24, 25, 26 , 27, 28, 29, 30, 31 and 35, further reverse phase liquid chromatography mass spectrometry (Method D) cycles are performed on the compounds derived from the coupling of the precursors mentioned in columns. Fractions containing the expected compound are evaporated, weighed, diluted to 10 mM and analyzed by reverse phase liquid chromatography mass spectrometry. The purified compound is characterized by retention time and molecular peak (table below).

  4). Cup of [5-methoxy-1-methyl-3- (1H-pyrrolo [2,3-b] pyridin-2-yl) -1H-indol-6-yloxy] acetic acid and precursors mentioned in columns 29 and 30 The compound derived from the ring is subjected to further reverse phase liquid chromatography mass spectrometry (Method D) cycles. Fractions containing the expected compound are evaporated, weighed, diluted to 10 mM and analyzed by reverse phase liquid chromatography mass spectrometry. The purified compound is characterized by retention time and molecular peak (table below).

(Example 139)
4- {2- [5-Methoxy-1-methyl-3- (1H-pyrrolo [2,3-b] pyridin-2-yl) -1H-indol-6-yloxy] acetylamino} -1-benzopyran- 8-Carboxylic acid [5-methoxy-1-methyl-3- (1H-pyrrolo [2,3-b] pyridin-2-yl) -1H-indol-6-yloxy] acetic acid (method described in Example 88) 4- {2- [5-methoxy-1-methyl-3- (1H-pyrrolo [2,3- b] pyridin-2-yl) -1H-indol-6-yloxy] -acetylamino} -1-benzopyran-8-carboxylic acid methyl ester in 1 mL of methanolic potassium hydroxide solution (potassium 0.1 g / methanol 1 mL) However, for 16 hours at room temperature. After evaporation of the solvent, the compound is diluted with a mixture of dimethyl sulfoxide (0.75 mL) and 12N aqueous hydrochloric acid (0.25 mL). The resulting solution is filtered and purified by reverse phase liquid chromatography mass spectrometry (Method F). 4- {2- [5-Methoxy-1-methyl-3- (1H-pyrrolo [2,3-b] pyridin-2-yl) -1H-indol-6-yloxy] acetylamino} -1-benzopyran- 8-carboxylic acid (0.0016 g, 30%) was isolated and its properties are as follows.

LC / MS analysis: tr = 3.5 min, m / z = 526.88 [M + H ^< + ^> ).

(Example 147)
2- [1-Methyl-5-methoxy-6- (2-morpholin-4-yl-ethoxy) -1H-indol-3-yl] -1H-pyrrolo [2,3-b] pyridine a) 2- [ 1-methyl-5-methoxy-6- (2-morpholin-4-ylethoxy) -1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H pyrrolo [2,3-b] pyridine 0 2- [1-methyl-5-methoxy-6- (2-morpholin-4-yl-ethoxy) by following the procedure described in Example 89a except using .24 g and 1.93 mL of 5N aqueous potassium hydroxide. -1H-Indol-3-yl] -1H-pyrrolo [2,3-b] pyridine is prepared. 0.116 g of 2- [1-methyl-5-methoxy-6- (2-morpholin-4-ylethoxy) -1H-indol-3-yl] -1H-pyrrolo [2,3-b] pyridine is obtained, Its characteristics are as follows.

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value) 2.50 to 2.65 (mt: 4H); 2.76 (t, J = 6 Hz: 2H); 3.60 (wide t , J = 5 Hz: 4H); 3.79 (s: 3H); 3.87 (s: 3H); 4.16 (t, J = 6 Hz: 2H); 6.73 (d, J = 1.5 Hz) : 1H); 6.99 (dd, J = 8 and 5 Hz: 1H); 7.16 (s: 1H); 7.42 (s: 1H); 7.77 (s: 1H); 7.82 ( Wide d, J = 8 Hz: 1H); 8.09 (dd, J = 5 and 1.5 Hz: 1H); 11.71 (wide s: 1H).

Mass spectrum (EI): m / z = 407 [M] ⁺ (reference peak).

  b) 2- [1-Methyl-5-methoxy-6- (2-morpholin-4-ylethoxy) -1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2, 3-b] -pyridine is prepared by the following method.

  2- [1-Methyl-5-methoxy-6- (2-iodoethoxy) -1H-indole-3 was charged with 0.11 g of potassium carbonate and 0.14 mL of morpholine at a temperature around 20 ° C. under an inert argon atmosphere. -Yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine is added to a solution of 0.24 g of acetonitrile (24 mL). The reaction medium is heated at 60 ° C. for 24 hours. After cooling, the reaction medium is concentrated under reduced pressure. The oil obtained is taken up with 10 mL of water and 10 mL of ethyl acetate. After separation by settling, the organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue is purified by flash-pack chromatography (silica, 30/70 volume ratio ethyl acetate / cyclohexane as eluent). Fractions containing product are concentrated under reduced pressure. 2- [1-Methyl-5-methoxy 6- (2-morpholin-4-ylethoxy) -1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b ] 0.24 g of pyridine is thus obtained, the properties of which are as follows:

Mass spectrum (CI): m / z = 561 [M + H] ⁺ (reference peak).

  c) 2- [1-Methyl-5-methoxy-6- (2-iodoethoxy) -1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b Pyridine is produced by the following method.

  0.260 g of sodium iodide was added to 2- [1-methyl-5-methoxy-6- (2-chloroethoxy) -1H-indol-3-yl] -1 at a temperature around 20 ° C. under an inert argon atmosphere. -(Toluene-4-sulfonyl) -1H-pyrrolo- [2,3-b] pyridine is added to a solution of 0.59 g of 2-butanone (42 mL). The reaction medium is refluxed for 24 hours. After cooling, the reaction medium is concentrated under reduced pressure. The resulting residue is purified by flash-pack chromatography (silica, methylene chloride as eluent). Fractions containing product are concentrated under reduced pressure. 2- [1-Methyl-5-methoxy-6- (2-iodoethoxy) -1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine 0.565 g is thus obtained, the properties of which are as follows:

Mass spectrum (EI): m / z = 601 [M] ⁺ , m / z = 446 (reference peak).

  d) 2- [1-Methyl-5-methoxy-6- (2-chloroethoxy) -1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b Pyridine is produced by the following method.

  0.101 g of sodium hydride (60% product in oil) was mixed with 2- [1-methyl-5-methoxy-6-hydroxy) -1H-indol-3-yl at a temperature close to 20 ° C. under an inert argon atmosphere. ]-(Toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine is added to a solution of 0.94 g of dimethylformamide (22 mL). The reaction medium is stirred at this temperature for 15 minutes. Next, 0.525 mL of 1-chloro-2-bromoethane is added. After stirring for 2 hours at the same temperature, 0.1 g of sodium hydride (60% in oil) and 0.525 mL of 1-chloro-2-bromoethane are added again. The reaction medium is maintained at this temperature for 20 hours with stirring. Add 20 mL water and 20 mL ethyl acetate. After separation by settling, the organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue is purified by flash-pack chromatography (silica, 35/65 volume ratio ethyl acetate / cyclohexane as eluent). Fractions containing product are concentrated under reduced pressure. 2- [1-Methyl-5-methoxy-6- (2-chloro-ethoxy) -1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] 0.596 g of pyridine is thus obtained, the properties of which are as follows:

Mass spectrum (EI): m / z = 509 [M] ⁺ , m / z = 354 (reference peak).

  e) 2- [1-Methyl-5-methoxy-6-hydroxy) -1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine, It is manufactured by the following method.

  0.798 mL of iodotrimethylsilane was added to 2- [1-methyl-5-methoxy-6-benzyloxy) -1H-indol-3-yl] -1- (toluene) at a temperature around 20 ° C. in an inert argon atmosphere. -4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine is added to a solution of 1.2 g of acetonitrile (90 mL). The reaction medium is heated at 50 ° C. for 4 hours. After cooling, add 60 mL water and 60 mL ethyl acetate. After separation by settling, the organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (silica, 40/60 volume ratio ethyl acetate / cyclohexane, argon as eluent). Fractions containing product are concentrated under reduced pressure. 0.825 g of 2- [1-methyl-5-methoxy-6-hydroxy) -1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine The properties thus obtained are as follows.

Mass spectrum (EI): m / z = 447 [M] ⁺ , m / z = 292 (reference peak).

  Compound 2- [1-Methyl-5-methoxy-6-benzyloxy) -1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine is patented Manufactured according to the method described in WO03000688A1.

(Example 148)
2- {1-Methyl-5-methoxy-6- [2- (4-methyl-piperazin-1-yl) ethoxy] -1H-indol-3-yl} -1H-pyrrolo- [2,3-b] Pyridine a) 2- [1-Methyl-5-methoxy-6- (2- (4-methylpiperazin-4-ylethoxy) -1H-indol-3-yl] -1- (toluene-4sulfonyl) -1H- By following the procedure described in Example 89a except that 0.195 g of pyrrolo [2,3-b] pyridine and 1.53 mL of 5N aqueous potassium hydroxide were used, 2- {1-methyl-5-methoxy-6- [ 2- (4-Methylpiperazin-1-yl) -ethoxy] -1H-indol-3-yl} -1H-pyrrolo [2,3-b] pyridine is prepared by flash-pack chromatography (silica, eluent). 90/10 volume ratio methylene chloride / methanol, argon) followed by 2- {1-methyl-5-methoxy-6- [2- (4-methylpiperazin-1-yl) -ethoxy] -1H- 0.086 g of indol-3-yl} -1H-pyrrolo [2,3-b] pyridine is obtained, the properties of which are as follows.

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value) 2.18 (s: 3H); 2.37 (undivided peak: 4H); 2.50 to 2.65 (mt: 4H) 2.78 (t, J = 6 Hz: 2H); 3.83 (s: 3H); 3.90 (s: 3H); 4.17 (t, J = 6 Hz: 2H); 6.77 (d 7.02 (dd, J = 8 and 5 Hz: 1H); 7.20 (s: 1H); 7.46 (s: 1H); 7.80 (s: 1H); 7.86 (wide dd, J = 8 and 1.5 Hz: 1H); 8.13 (dd, J = 5 and 1.5 Hz: 1H); 11.75 (wide s: 1H).

Mass spectrum (EI): m / z = 419 [M] ⁺ , m / z = 127 (reference peak).

  b) 0.1 mL N-methylpiperazine and 2- [1-methyl-5-methoxy-6- (2-iodoethoxy) -1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H 2- [1-Methyl-5-methoxy-6- (2- (4-methylpiperazine-) by following the procedure described in Example 147b except using 0.27 g of pyrrolo [2,3-b] pyridine. 4-yl-ethoxy) -1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine is prepared by flash-pack chromatography (silica, elution After purification with 90/10 volume ratio methylene chloride / methanol, argon as a liquid, 2- [1-methyl-5-methoxy-6- (2- (4-methylpiperazin-4-yl-ethoxy) )-1H-indol-3-yl] -1- (toluene-4-sulfonyl)-1H-pyrrolo [2,3-b] pyridine 0.197g was obtained, the characteristics are as follows.

Mass spectrum (EI): m / z = 573 [M] ⁺ , m / z = 127 (reference peak).

(Example 149)
1- {2- [1-Methyl-5-methoxy-3- (1H-pyrrolo [2,3-b] pyridin-2-yl) -1H-indol-6-yloxy] ethyl} piperidin-4-ol a ) 1- {2- [1-Methyl-5-methoxy-3- (1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridin-2-yl) -1H-indole-6 1- {2- [1-Methyl-5-methoxy] by following the procedure described in Example 89a except using 0.23 g of -yloxy] ethyl} piperidin-4-ol and 1.8 mL of 5N aqueous potassium hydroxide. -3- (1H-pyrrolo [2,3-b] pyridin-2-yl) -1H-indol-6-yloxy] ethyl} piperidin-4-ol is prepared. After purification by flash-pack chromatography (silica, 90/10 volume ratio methylene chloride / methanol, argon as eluent), 1- {2- [5-1-methylmethoxy-3- (1H-pyrrolo [2,3 -B] pyridin-2-yl) -1H-indol-6-yloxy] ethyl} piperidin-4-ol 0.017 g is obtained, the properties of which are as follows.

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value): 1.41 (mt: 2H); 1.72 (very wide d, J = 12 Hz: 2H); 2.16 (wide t 2.73 (t, J = 6 Hz, 2H); 2.84 (mt: 2H); 3.45 (mt: 1H); 3.81 (s: 3H); 88 (s: 3H); 4.13 (t, J = 6 Hz: 2H); 4.55 (d, J = 4 Hz: 1H); 6.75 (wide d, J = 2 Hz: 1H); 7.00 (Dd, J = 8 and 5 Hz: 1 H); 7.16 (s: 1 H); 7.42 (s: 1 H); 7.77 (s: 1 H); 7.84 (wide d, J = 8 Hz: 1H); 8.12 (wide dd, J = 5 and 1.5 Hz: 1H); 11.73 (wide s: 1H).

Mass spectrum (EI): m / z = 420 [M] ⁺ , m / z = 128 (reference peak).

  b) 0.089 g of 4-hydroxypiperidine and 2- [1-methyl-5-methoxy-6- (2-iodoethoxy) -1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H 1- {2- [1-Methyl-5-methoxy-3- (1- (toluene-) by following the procedure described in Example 147b except using 0.265 g of pyrrolo [2,3-b] pyridine. 4-sulfonyl) -1H-pyrrolo [2,3-b] pyridin-2-yl) -1H-indol-6-yloxy] ethyl} -piperidin-4-ol is prepared. After purification by flash-pack chromatography (silica, 90/10 volume ratio methylene chloride / methanol, argon as eluent), 1- {2- [1-methyl-5-methoxy-3- (1- (toluene-4 -Sulfonyl) -1H-pyrrolo [2,3-b] pyridin-2-yl) -1H-indol-6-yloxy] ethyl} -piperidin-4-ol, 0.234 g, which has the following properties: Street.

Mass spectrum (CI): m / z = 575 [M + H] ⁺ (reference peak).

(Examples 150 to 159)
a) 2- [6- (2-Iodoethoxy) -5-methoxy-1-methyl-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b Pyridine is produced by the following method.

  2- [6- (2-Chloroethoxy) -5-methoxy-1-methyl-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b]- A solution of pyridine (0.660 g, 1,294 μmol) in methyl ethyl ketone (10 mL) is placed in a 50 mL one-necked flask and sodium iodide (0.29 g; 1.941 mmol) is added. The reaction mixture is refluxed for 16 hours. Analysis by thin layer chromatography (50/50 cyclohexane / ethyl acetate) indicates that the reaction is complete. After returning to 20 ° C., the reaction mixture is evaporated under reduced pressure and the residue is taken up in a mixture of water (50 mL) and methylene chloride (50 mL), which is separated by settling. The organic extract is washed with water (30 mL) and dried over magnesium sulfate. After evaporation of the solvent, the resulting compound is chromatographed on silica gel (cartridge FC-10-Si-BP-Sup, 10 g of silica with a particle size of 15-35 μm, elution is carried out with a 70/30 mixture of cyclohexane / ethyl acetate) Purify by Fractions containing the expected compound were combined and evaporated under reduced pressure to give 2- [6- (2-iodoethoxy) -5-methoxy-1-methyl-1H-indol-3-yl] -1- ( Toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine (0.695 g; 89%) was obtained, the properties of which are as follows:

LC / MS analysis: tr = 4.0, m / z = 601.96 [M + H] ⁺ .

  b) 2- [6- (2-Chloroethoxy) -5-methoxy-1-methyl-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b Pyridine is produced by the following method.

  5-methoxy-1-methyl-3- [1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridin-2-yl] -1H-indol-6-ol (0.8 g; 1.788 mmol) in dimethylformamide (5 mL) is placed in a 50 mL round bottom flask inerted with argon and sodium hydride (0.064 g; 2.146 mmol) is added. The reaction mixture becomes brown and 1-bromo-2-chloroethane (0.308 g; 2.146 mmol) is added. The reaction mixture is stirred at 20 ° C. for 1 h 30 and sodium hydride (0.064 g; 2.146 mmol) and 1-bromo-2-chloroethane (2 × 0.5 mL) are added again. Analysis by thin layer chromatography (50/50 cyclohexane / ethyl acetate) indicates that the reaction is complete. The reaction mixture is diluted with water (150 mL) and ethyl acetate (50 mL) and extracted with ethyl acetate (2 × 50 mL). The organic extracts were combined, dried over magnesium sulfate, filtered and evaporated under reduced pressure to give the crude compound which was chromatographed on silica gel (AIT cartridge FC25Si-BP-Sup, eluent: 65 / 35 cyclohexane / ethyl acetate, 10 mL / min). Fractions containing the expected compound were combined and evaporated under reduced pressure to give the expected 2- [6- (2-chloroethoxy) -5-methoxy-1-methyl-1H-indol-3-yl] -1 -(Toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine (0.66 g; 72%) is obtained in the form of a powder, the properties of which are as follows:

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value) 2.30 (s: 3H); 3.75 (s: 3H); 3.87 (s: 3H); 4.04 (wide) t, J = 5 Hz: 2H); 4.36 (wide t, J = 5 Hz, 2H); 6.75 (s: 1H); 6.99 (s: 1H); 7.20 (s: 1H); 7.26 (wide d, J = 9 Hz: 2H); 7.30 (dd, J = 8 and 5 Hz: 1H); 7.54 (d, J = 9 Hz: 2H); 7.59 (wide s: 1H) ); 7.94 (dd, J = 8 and 1.5 Hz: 1H); 8.35 (dd, J = 5 and 1.5 Hz: 1H).

c) Alkylation of Examples 150-159 In 10 glass reactors (1.3 × 10 cm), each amine in the following table is weighed and dissolved in dimethylformamide (0.5 mL). 2- [6- (2-Iodoethoxy) -5-methoxy-1-methyl-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine (0.05 g / reactor, 83 μmol / reactor) of dimethylformamide (0.5 mL / reactor) and then potassium carbonate (0.035 g / reactor, 249 μmol / reactor) are added to the solution. The reactor is sealed and placed in a 60 ° C. oil bath for 4 hours 30 minutes. The contents of each reactor were filtered and solid conditioned extraction cartridge (Varian Mega Bond Elut-SCX), preconditioned with methanol (12 mL), reference number: 12256011, 1 g, 6 mL, batch 172802, unresolved peak G (UNRESOLVED PEAKG) code 3102). The solid phase extraction cartridge is eluted with methanol (2 x 6 mL) and then with methanol / 2M ammonia (2 x 6 mL). The ammonia-containing elution fractions are combined and the solvent is distilled off to obtain the crude compound. The crude compound was purified by chromatography on silica gel (24 mL cartridge containing 10 g of 40-60 μm silica gel with methylene chloride) and the elution was varied in each case but adapted in each case (97/3 to 80/20). ) Methylene chloride / methanol mixture. Fractions containing the expected compound are combined and evaporated to give the corresponding intermediate compound that is used in the detosylation step.

d) Deprotection of Examples 150-159 Methanolic potassium hydroxide solution (1.5 mL / tube, potassium hydroxide 0.1 g / methanol 1 mL) was added to 10 dissolved blood vessels containing the compound derived from the above reaction. (1.3 × 10 cm) and the tube is stirred at 20 ° C. for 16 hours. After evaporating the solvent under reduced pressure, the residue was taken up in dimethylformamide (0.6 mL) and the solution so obtained was preconditioned with methanol (2 × 6 mL) solid phase extraction cartridge (Varian Mega. Elute with Bond Elute, SCX, 2 g, 6 mL, reference number 19102). After the first elution with methanol (6 mL), the cartridge is eluted with 2N ammoniacal methanol (5 mL) and the ammonia-containing eluent is evaporated to dryness. The compound thus obtained was finally purified by chromatography on silica gel (40-60 μm silica gel 2 g cartridge, methylene chloride), elution at 5 mL / min with methylene chloride and 2M ammoniacal methanol (95/5 ). Fractions containing the expected compound are combined and evaporated under reduced pressure to give the expected compound. Each compound is dissolved in dimethylformamide (0.6 mL) and eluted with a solid phase extraction cartridge (Varian Mega Bond Elut, SCX, 0.5 g, 3 mL) preconditioned with methanol (2 × 3 mL). After initial elution with methanol (4.8 mL), the cartridge is eluted with 2N ammoniacal methanol (4.8 mL) and the ammonia-containing eluent is evaporated to dryness to give the expected compound, which is reversed. Characterized by phase liquid chromatography mass spectrometry (Method A). Retention times and molecular ions are reported in the table below.

(Examples 160 to 164)
a) 2- [6- (3-Iodopropoxy) -5-methoxy-1-methyl-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b Pyridine is produced by the following method.

  2- [6- (3-Chloropropoxy) -5-methoxy-1-methyl-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo- [2,3-b] Pyridine (0.415 g; 792 μmol) in methyl ethyl ketone (10 mL) is placed in a 50 mL one-necked flask and sodium iodide (0.178 g; 1.18 mmol) is added. The reaction mixture is refluxed for 16 hours. Analysis by thin layer chromatography (50/50 cyclohexane / ethyl acetate) shows that the raw material is still present. Additional sodium iodide (0.178 g; 1.18 mmol) is introduced and reflux is maintained for 3 hours. After returning to 20 ° C., the precipitate is dissolved in methylene chloride (200 mL), washed with water (50 mL), and dehydrated with magnesium sulfate. After evaporation of the solvent, the residue is taken up in ethyl acetate (20 mL). Insoluble materials are removed, and the filtrate is evaporated under reduced pressure. 2- [6- (3-Iodopropoxy) -5-methoxy-1-methyl-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine (0.367 g; 75%) was isolated and its properties are as follows:

LC / MS analysis: tr = 4.32 min; m / z = 615.96 [M + H] ⁺ .

  b) 2- [6- (3-Chloropropoxy) -5-methoxy-1-methyl-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b Pyridine is produced by the following method.

  5-methoxy-1-methyl-3- [1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridin-2-yl] -1H-indol-6-ol (0.45 g; A solution of 1.006 mmol) in dimethylformamide (5 mL) is placed in a 50 mL round bottom flask inerted with argon and sodium hydride (0.06 g; 2.01 mmol) is added. The reaction mixture becomes dark and 1-bromo-3-chloropropane (0.199 mL, 2.01 mmol) is added. The reaction mixture is stirred at 20 ° C. for 30 minutes. The reaction mixture is diluted with methylene chloride (50 mL) and water (100 mL), separated by settling and extracted with methylene chloride (2 × 50 mL). The organic extracts are combined, dried over magnesium sulfate, filtered, and evaporated under reduced pressure to give an oil. The oil is taken up in diisopropyl ether (10 mL), triturated and the crystals discarded. After filtration, washing with diisopropyl ether and vacuum drying, 2- [6- (3-chloropropoxy) -5-methoxy-1-methyl-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine was isolated in the form of ocher crystals (0.415 g; 79%) and its properties are as follows.

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value): 2.27 (mt: 2H); 2.30 (s: 3H); 3.75 (s: 3H); 3.87 ( 3.89 (t, J = 6.5 Hz: 2H); 4.20 (t, J = 6.5 Hz: 2H); 6.74 (s: 1H); 6.97 (s: 7.19 (s: 1H); 7.26 (wide d, J = 8.5 Hz: 2H); 7.29 (dd, J = 8 and 5 Hz: 1H); 7.50 (s: 1H) 7.57 (d, J = 8.5 Hz: 2H); 7.93 (dd, J = 8 and 1.5 Hz: 1H); 8.34 (dd, J = 5 and 1.5 Hz: 1H) .

c) Alkylation of Examples 160 to 164 In 5 1.2 × 10 cm lysed blood vessels, 5 types of amines described in the following table are weighed and dissolved in dimethylformamide (0.5 mL). 2- [6- (3-Iodopropoxy) -5-methoxy-1-methyl-1H-indol-3-yl] -1 (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine ( 81.2 μmol / tube) of dimethylformamide (0.5 mL / tube) solution is placed in five lysing tubes (1.2 × 10 cm), and the following amine solution is added to the solution. Potassium carbonate (0.035 g / tube) is added using a spatula. The reactor is sealed and heated at 65 ° C. with stirring for 3 hours. After returning to room temperature, the contents of each reactor are filtered and the filtrate is purified by reverse phase liquid chromatography mass spectrometry (2 injections per sample, Method B). Fractions containing the expected compound are combined and evaporated under reduced pressure to give the compound, which is used in the next step.

d) Detosylation of Examples 160-164 Methanolic potassium hydroxide solution (1.6 mL / tube, potassium hydroxide 0.1 g / methanol 1 mL solution) was dissolved in 5 solutions containing the compound obtained above. In addition to the blood vessels (1.2 × 10 cm), the mixture is stirred at 20 ° C. for 16 hours and then evaporated to dryness. The evaporated residue is taken up in a mixture of dimethylformamide (0.8 mL) and acetic acid (0.2 mL) and purified by reverse phase liquid chromatography mass spectrometry (Method B, 2 injections per sample). Fractions containing the expected compound are combined and eluted with a solid phase extraction cartridge (Varian Mega Bond Elut-SCX, 1 g, 6 mL) preconditioned with methanol (2 × 6 mL). After elution with methanol (2 x 6 mL) and then elution with 2N ammoniacal methanol (2 x 6 mL), the ammonia-containing eluates are combined and evaporated under reduced pressure. The dry extract is taken up in a mixture of methylene chloride and methanol (90/10) and filtered through a silica cartridge (Thermoquest, Hypersep silica, 0.1 g, # 60300-494). The eluate is evaporated under reduced pressure to give the expected compound, which is characterized by retention time and molecular peak.

(Examples 165 to 167)
a) 2- {6- [2- (2-Chloroethoxy) ethoxy] -5-methoxy-1-methyl-1H-indol-3-yl} -1- (toluene-4-sulfonyl) -1H-pyrrolo [ 2,3-b] -pyridine is prepared by the following method.

  2- {6- [2- (2-Chloroethoxy) ethoxy] -5-methoxy-1-methyl-1H-indol-3-yl} -1- (toluene-4-sulfonyl) -1H-pyrrolo [2, 3-b] Pyridine (0.145 g, 261.7 μmol) in methyl ethyl ketone (3 mL) is placed in a 50 mL one-necked flask and sodium iodide (0.118 g; 785 μmol) is added. The reaction mixture is refluxed for 16 hours. Analysis by thin layer chromatography (50/50 cyclohexane / ethyl acetate) indicates that the raw material is still present. Additional sodium iodide (0.178 g; 1.18 mmol) is introduced and reflux is maintained for 3 hours. After returning to 20 ° C., the precipitate is dissolved in methylene chloride (30 mL), washed with water (10 mL), and dehydrated with magnesium sulfate. After evaporation of the solvent, the residue is taken up in diisopropyl ether (10 mL). The resulting solid is removed and the filtrate is evaporated under reduced pressure. 2- {6- [2- (2-Chloroethoxy) ethoxy] -5-methoxy-1-methyl-1H-indol-3-yl} -1- (toluene-4-sulfonyl) -1H-pyrrolo [2, 3-b] pyridine (0.137 g; 81%) is isolated and used as such.

  b) 2- {6- [2- (2-Chloroethoxy) ethoxy] -5-methoxy-1-methyl-1H-indol-3-yl} -1- (toluene-4-sulfonyl) -1H-pyrrolo [ 2,3-b] -pyridine is prepared by the following method.

  5-methoxy-1-methyl-3- [1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridin-2-yl] -1H-indol-6-ol (2.998 g; 670 μmol) of dimethylformamide (3 mL) is placed in a 10 mL round bottom flask, sodium hydride (0.603 g; 2.01 mmol) is added and the mixture is stirred for 5 minutes. The reaction mixture becomes green and bis (2-chloroethyl) ether (0.235 mL; 2.01 mmol) is added. The reaction mixture is stirred at 20 ° C. for 1 hour 30 minutes. Analysis by thin layer chromatography (50/50 cyclohexane / ethyl acetate) indicates that the starting compound is consumed. The reaction mixture is taken up in water (30 mL) and extracted with methylene chloride (20 mL). The organic extracts were combined, dried over magnesium sulfate, filtered, and evaporated under reduced pressure to give the crude compound, which was chromatographed on silica gel (AIT cartridge, flash silica column, 20-40 μm, 25 g, Reference number: FC-25SI-BP-SUP, 10 mL / min, 70/30 to 50/50 cyclohexane / ethyl acetate). Fractions containing the expected compound were combined and evaporated under reduced pressure to give 2- {6- [2- (2-chloroethoxy) ethoxy] -5-methoxy-1-methyl-1H-indol-3-yl. } -1- (Toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine (0.145 g; 39%) is obtained and used as such in the next step.

c) Alkylation of Examples 165 to 167 The amines listed in the table below are placed in 3 lysis vessels (1.2 x 10 cm) and dissolved in dimethylformamide (1 mL / tube). 2- {6- [2- (2-Chloroethoxy) ethoxy] -5-methoxy-1-methyl-1H-indol-3-yl} -1- (toluene-4-sulfonyl) -1H-pyrrolo [2, 3-b] A solution of pyridine (0.032 g / tube, 50 μmol / reactor) was placed in four lysis vessels (1.2 × 10 cm) and each of the amine solutions and potassium carbonate (0.021 g; 150 μmol / tube). ). The reactor is sealed and heated at 65 ° C. with stirring for 6 hours. After returning to 20 ° C., the contents of each tube are filtered and diluted with acetic acid (0.2 mL). The solution so obtained is eluted with a solid phase extraction cartridge (Varian, Mega Bond Elut, SCX, 2 g, 6 mL, # 19102) preconditioned with methanol (2 × 6 mL). After the first elution with methanol (6 mL), the cartridge is eluted with 2N ammoniacal methanol (5 mL) and the ammonia-containing eluent is evaporated to dryness to give the expected compound, which is used in the next step Used in.

d) Detosylation of Examples 165 to 167 Methanolic potassium hydroxide solution (1.5 mL, potassium hydroxide 0.1 g / methanol 1 mL solution) was added to 3 tubes (3 mL) containing the compound obtained above ( 1.2 × 10 cm) and each reaction mixture is stirred at 20 ° C. for 16 hours. The contents of each tube was diluted with acetic acid (0.2 mL) and preconditioned with methanol (2 × 6 mL) extraction cartridge (Varian, Mega Bond Elut, SCX, 2 g, 6 mL, reference number 19102, batch 1706002 ). After first eluting with methanol (6 mL), the cartridge was eluted with 2N ammoniacal methanol (2 × 5 mL), the ammonia-containing eluent was evaporated to dryness and each sample was dimethyl sulfoxide (0.5 mL). ) And purified by reverse phase liquid chromatography mass spectrometry (Method G). Fractions containing the expected compound are combined and evaporated under reduced pressure to give the expected compound. Fractions were loaded onto a SCX cartridge (Varian Mega Bond Elut-SCX cartridge, reference number: 12256011, 1 g, 6 mL, batch 1728002, unresolved peak G code 3102) preconditioned with methanol (twice with 6 mL) To do. After elution with methanol (2 x 6 mL), the cartridge was eluted with 2N ammoniacal methanol (2 x 6 mL) and the ammonia-containing eluent was evaporated under reduced pressure to give the expected compound, which was retained for a retention time And characterized by peak (table below).

(Example 168)
2- [5-Methoxy-6- (2-methoxyethoxy) -1-methyl-1H-indol-3-yl] -1H-pyrrolo [2,3-b] pyridine a) 2- [5-methoxy-6 -(2-Methoxyethoxy) -1-methyl-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine (0.102 g) and 5N potassium hydroxide By following the procedure described in Example 89a except using 0.80 mL, 2- [5-methoxy-6- (2-methoxyethoxy) -1-methyl-1H-indol-3-yl] -1H-pyrrolo [2,3-b] pyridine is prepared. After purification by flash-pack chromatography (silica, 92.5 / 7.5 volume ratio methylene chloride / methanol, argon as eluent), 2- [5-methoxy-6- (2-methoxyethoxy) -1-methyl 0.033 g of -1H-indol-3-yl] -1H-pyrrolo [2,3-b] pyridine is obtained, the properties of which are as follows.

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value) 3.39 (s: 3H); 3.76 (mt: 2H); 3.83 (s: 3H); 3.91 (s : 3H); 4.21 (mt: 2H); 6.78 (d, J = 2 Hz: 1H); 7.04 (dd, J = 8 and 5 Hz: 1H); 7.17 (s: 1H); 7.46 (s: 1H); 7.80 (s: 1H); 7.88 (dd, J = 8 and 1.5 Hz: 1H); 8.13 (dd, J = 5 and 1.5 Hz: 1H) ); 11.75 (wide s: 1H). Mass spectrum (EI): m / z = 351 [M] ⁺ (reference peak).

  b) 2- [1-Methyl-5-methoxy-6-hydroxy] -1H using 0.195 g of 1-bromo-2-methoxyethane instead of 1-chloro-2-bromoethane used in Example 147d -Indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine except that 0.224 g was used to follow the procedure described in Example 147d to give 2- [ 5-methoxy-6- (2-methoxyethoxy) -1-methyl-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine is prepared. . After purification by flash-pack chromatography (silica, 80/20 volume ratio ethyl acetate / cyclohexane, argon as eluent), 2- [5-methoxy-6- (2-methoxyethoxy) -1-methyl-1H-indole 0.121 g of -3-yl] -1H-pyrrolo [2,3-b] pyridine is obtained, the properties of which are as follows.

Mass spectrum (EI): m / z = 505 [M] ⁺ (reference peak).

(Example 169)
2- [5-Methoxy-6- (2-hydroxyethoxy) -1-methyl-1H-indol-3-yl] -1H-pyrrolo [2,3-b] pyridine a) 2- [5-methoxy-6 -(2-acetyloxyethoxy) -1-methyl-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine 0.5 g and 5N hydroxylation 2- [5-Methoxy-6- (2-hydroxyethoxy) -1-methyl-1H-indol-3-yl] -1H was obtained by following the procedure described in Example 89a except using 8.43 mL of aqueous potassium solution. -Produce pyrrolo [2,3-b] pyridine. After purification by flash-pack chromatography (silica, 95/05 volume ratio methylene chloride / methanol, argon as eluent), 2- [5-methoxy-6- (2-hydroxyethoxy) -1-methyl-1H-indole 0.13-g of -3-yl] -1H-pyrrolo [2,3-b] pyridine is obtained, the properties of which are as follows.

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value) 3.75 to 3.85 (mt: 2H); 3.82 (s: 3H); 3.90 (s: 3H); 4 0.09 (t, J = 5.5 Hz: 2H); 4.88 (wide t, J = 5 Hz: 1H); 6.76 (d, J = 2 Hz: 1H); 7.02 (dd, J = 8 7.15 (s: 1H); 7.44 (s: 1H); 7.79 (s: 1H); 7.86 (wide dd, J = 8 and 1.5 Hz: 1H) 8.12 (dd, J = 5 and 1.5 Hz: 1H); 12.24 (undivided peak: 1H). Mass spectrum (EI): m / z = 337 [M] ⁺ (reference peak).

  b) 0.246 mL of ethyl 2-bromoacetate and 2- [1-methyl-5-methoxy-6-hydroxy] -1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [ By following the procedure described in Example 147d except that 0.5 g of 2,3-b] pyridine was used, 2- [5-methoxy-6- (2-acetyloxyethoxy) -1-methyl-1H-indole- 3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine is prepared. After purification by flash-pack chromatography (silica, 40/60 volume ratio ethyl acetate / cyclohexane as eluent), 2- [5-methoxy-6- (2-acetyloxyethoxy) -1-methyl-1H-indole- 0.56 g of 3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine is obtained, the properties of which are as follows.

Mass spectrum (EI): m / z = 533 [M] ⁺ , m / z = 292 (reference peak).

(Example 170)
2- (5-methoxy-1,6-dimethyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyridine a) 2- (5 methoxy-1,6-dimethyl-1H-indole Procedure described in Example 89a except that 0.028 g of 3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine and 0.283 mL of 5N aqueous potassium hydroxide are used. To produce 2- (5-methoxy-1,6-dimethyl-1H-indol-3-yl) -1H-pyrrolo- [2,3-b] pyridine. 0.01 g of 2- (5-methoxy-1,6-dimethyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] -pyridine is obtained, the properties of which are as follows: .

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value) 2.33 (s: 3H); 3.83 (s: 3H); 3.94 (s: 3H); 6.78 (d 7.03 (dd, J = 8 and 5 Hz: 1H); 7.35 (wide s: 1H); 7.40 (wide s: 1H); 7.84 (s: 1H) ); 7.87 (wide dd, J = 8 and 1.5 Hz: 1H); 8.12 (dd, J = 5 and 1.5 Hz: 1H); 11.78 (wide s: 1H).

Mass spectrum (ES +): m / z = 292 [M + H] ⁺ (reference peak).

  b) 2- (5-Methoxy-1,6-dimethyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine is prepared by the following method. Manufactured by.

  0.012 g of methyl boronic acid, 0.0715 g of potassium carbonate and 0.020 g of tetrakis (triphenylphosphine) palladium were added to 2- [1-methyl-5-methoxy-6- (trifluorosulfonyloxy) -1H-indol-3-yl ] 1- (Toluene-4sulfonyl) -1H-pyrrolo [2,3-b] pyridine is added to a solution of 0.1 g of dehydrated dioxane (3 mL) at a temperature around 20 ° C. under an inert argon atmosphere. The reaction medium is heated at 120 ° C. for 24 hours. After cooling, add 5 mL water and 5 mL ethyl acetate. After separation by settling, the organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue is purified by flash-pack chromatography (silica, 30/70 volume ratio ethyl acetate / cyclohexane as eluent). Fractions containing product are concentrated under reduced pressure. 0.03 g of 2- (5-methoxy-1,6-dimethyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine was The properties obtained are as follows.

Mass spectrum (EI): m / z = 445 [M] ⁺ , m / z = 290 (reference peak).

  c) 2- [1-Methyl-5-methoxy-6- (trifluorosulfonyloxy) -1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b ] -Pyridine is produced by the following method.

  0.451 mL of triflic anhydride and 1.35 mL of pyridine were added to 2- [1-methyl-5-methoxy-6-hydroxy-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo. -To a solution of 1 g of [2,3-b] pyridine in methylene chloride (30 mL) under an inert argon atmosphere at a temperature around 0 ° C. The reaction medium is stirred at this temperature for 3 hours. Remove the ice bath. After returning to a temperature around 20 ° C., 15 mL of water is added. After separation by settling, the organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue is purified by flash-pack chromatography (silica, methylene chloride as eluent). Fractions containing product are concentrated under reduced pressure. 2- [1-Methyl-5-methoxy-6- (trifluorosulfonyloxy) -1-H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b ] 1.12 g of pyridine are thus obtained, the properties of which are as follows:

Mass spectrum (CI): m / z = 580 [M + H] ⁺ (reference peak).

  The compound 2- [1-methyl-5-methoxy-6-hydroxy-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine is Manufactured according to the method described in 147e.

(Example 171)
4-chloro-2- {1-methyl-5-methoxy-6- [2- (4-methylpiperazin-1-yl) ethoxy] -1H-indol-3-yl} -1H-pyrrolo- [2,3 -B] -pyridine a) 4-chloro-2- [1-methyl-5-methoxy-6- (2- (4-methylpiperazin-4-yl-ethoxy) -1H-indol-3-yl] -1 By following the procedure described in Example 89a except using 0.300 g of-(toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] -pyridine and 2.22 mL of 5N aqueous potassium hydroxide solution, 4- Chloro-2- {1-methyl-5-methoxy-6- [2- (4-methylpiperazin-1-yl) ethoxy] -1H-indol-3-yl} -1H-pyrrolo [2,3-b] Prepare pyridine 4-chloro 2- {1-methyl-5-methoxy-6- [2- (4-methylpiperazin-1-yl) ethoxy] -1H-indol-3-yl} -1H-pyrrolo [2,3-b] pyridine 0 .169 g is obtained, the properties of which are as follows:

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value) 2.17 (s: 3H); 2.36 (undivided peak: 4H); 2.45 to 2.60 (mt: 4H) 2.77 (t, J = 6.5 Hz: 2H); 3.84 (s: 3H); 3.90 (s: 3H); 4.16 (t, J = 6.5 Hz: 2H); 6 7.11 (wide s: 1H); 7.14 (d, J = 5 Hz: 1H); 7.21 (s: 1H); 7.44 (s: 1H); 7.85 (s: 1H); 8 .08 (d, J = 5 Hz: 1H); 12.16 (undivided peak: 1H).

Mass spectrum (EI): m / z = 453 [M] ⁺ , m / z = 127 (reference peak).

  b) 0.087 mL N-methylpiperazine and 4-chloro-2- [1-methyl-5-methoxy-6- (2-iodoethoxy) -1H-indol-3-yl] -1- (toluene-4- By following the procedure described in Example 147b except using 0.25 g of sulfonyl) -1H-pyrrolo [2,3-b] pyridine, 4-chloro-2- [1-methyl-5-methoxy-6- ( 2-Methoxyethoxy) -1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] -pyridine is prepared. 4-chloro-2- [1-methyl-5-methoxy-6- (2- (4-methylpiperazin-4-yl-ethoxy) -1H-indol-3-yl] -1- (toluene-4-sulfonyl) ) -1H-pyrrolo [2,3-b] pyridine 0.303 g is obtained, the properties of which are as follows:

Mass spectrum (EI): m / z = 607 [M] ⁺ , m / z = 127 (reference peak).

  c) 4-Chloro-2- [1-methyl-5-methoxy-6- (2-chloroethoxy) -1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2 , 3-b] pyridine and following the procedure described in Example 147c except using 1.950 g of sodium iodide and 4-chloro-2- [1-methyl-5-methoxy-6- (2 -Iodoethoxy) -1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] -pyridine is prepared. After purification by flash chromatography (silica, 40/60 volume ratio ethyl acetate / cyclohexane, argon as eluent), 4-chloro-2- [1-methyl-5-methoxy-6- (2-iodoethoxy) -1H -Indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine 1.21 g is obtained, the properties of which are as follows:

Mass spectrum (EI): m / z = 635 [M] ⁺ , m / z = 480 (reference peak).

d) 4-Chloro-2- [1-methyl-5-methoxy-6-hydroxy) -1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b By following the procedure described in Example 147d except that 1.3 g of pyridine and 0.675 cm ^{3 of} 1-bromo-2-chloroethane were used, 4-chloro-2- [1-methyl-5-methoxy-6- ( 2-Chloroethoxy) -1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] -pyridine is prepared. After purification by flash chromatography (silica, 40/60 volume ratio ethyl acetate / cyclohexane, argon as eluent), 4-chloro-2- [1-methyl-5-methoxy-6- (2-chloroethoxy) -1H -Indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine 1.16 g is obtained, the properties of which are as follows.

Mass spectrum (CI): m / z = 544 [M + H] ⁺ (reference peak).

  e) 4-Chloro-2- [1-methyl-5-methoxy-6-benzyloxy) -1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3- b] 4-chloro-2- [1-methyl-5-methoxy-6-hydroxy) -1H- by following the procedure described in Example 147e except using 1.8 g of pyridine and 1.124 mL of iodotrimethylsilane. Indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine is prepared. After purification by flash chromatography (silica, 40/60 volume ratio ethyl acetate / cyclohexane, argon as eluent), 4-chloro-2- [1-methyl-5-methoxy-6-hydroxy) -1H-indole-3 1.3 g of -yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine are obtained, the properties of which are as follows:

Mass spectrum (CI): m / z = 482 [M + H] ⁺ (reference peak).

  f) 4-chloro-2- (5-methoxy-6-benzyloxy-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine By following the procedure described in Example 89c except using 5 g and 0.335 mL of methyl iodide, 4-chloro-2- [1-methyl-5-methoxy-6-benzyloxy) -1H-indole-3- Yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine. After purification by flash chromatography (silica, 40/60 volume ratio ethyl acetate / cyclohexane, argon as eluent) 4-chloro-2- (1-methyl-5-methoxy-6-benzyloxy-1H-indole-3 2.1 g of -yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine are obtained, the properties of which are as follows:

Mass spectrum (CI): m / z = 571 [M] ⁺ , m / z = 480 (reference peak).

  g) 2.75 g of 1-tert-butyloxycarbonyl-5-methoxy-6-benzyloxy-indole-3-boronic acid and 1- (toluene-4-sulfonyl) -1H-2-iodo-4-chloro-pyrrolo 4-Chloro-2- (5-methoxy-6-benzyloxy-1H-indol-3-yl) -1 by following the procedure described in Example 97c except using 3 g of [2,3-b] pyridine. -(Toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine is prepared. After purification by flash chromatography (silica, 40/60 volume ratio ethyl acetate / cyclohexane, argon as eluent), 4-chloro-2- (5-methoxy-6-benzyloxy-1H-indol-3-yl)- 2.53 g of 1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine is obtained, the properties of which are as follows:

Mass spectrum (EI): m / z = 557 [M] ⁺ , m / z = 466 (reference peak).

  Compounds 1- (toluene-4-sulfonyl) -1H-2-iodo-4-chloro-pyrrolo [2,3-b] pyridine and 1-tert-butyloxy-carbonyl-5-methoxy-6-benzyloxyindole-3 -Boronic acid is produced according to the method described in patent WO03000688A1.

(Example 172)
4-chloro-2- {1-methyl-5-methoxy-6- [2- (4-piperidylpiperidin-1-yl) ethoxy] -1H-indol-3-yl] -1H-pyrrolo [2,3- b] Pyridine a) 4-Chloro-2- [1-methyl-5-methoxy-6- (2- (4-piperidylpiperidin-1-yl) -ethoxy) -1H-indol-3-yl] -1- By following the procedure described in Example 89a except using 0.41 g of (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine and 2.73 mL of 5N aqueous potassium hydroxide solution, 4-chloro- 2- {1-Methyl-5-methoxy-6- [2- (4-piperidyl-piperidin-1-yl) ethoxy] -1H-indol-3-yl] -1H-pyrrolo [2,3-b] pyridine Manufacturing. 4-Chloro-2-15-methoxy-1-methyl-6- [2- (4-piperidylpiperidin-1-yl) ethoxy] -1H-indol-3-yl} -1H-pyrrolo [2,3-b ] 0.272 g of pyridine is obtained, the properties of which are as follows:

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value) 1.30 to 1.60 (mt: 8H); 1.70 (wide d, J = 12 Hz: 2H); 2.05 (wide) 2.18 (wide tt, J = 12, and 3.5 Hz: 1H); 2.46 (mt: 4H); 2.75 (t, J = 6 Hz: 2H); 3 .04 (wide d, J = 11 Hz: 2H); 3.83 (s: 3H); 3.90 (s: 3H); 4.15 (t, J = 6 Hz: 2H); 6.71 (wide s) 7.15 (dd, J = 5.5 Hz: 1H); 7.20 (s: 1H); 7.44 (s: 1H); 7.85 (s: 1H); d, J = 5.5 Hz: 1H); 12.14 (wide s: 1H).

Mass spectrum (EI): m / z = 521 [M] ⁺ , m / z = 195 (reference peak).

  b) 0.212 g 4-piperidinopiperidine and 4-chloro-2- [1-methyl-5-methoxy-6- (2-iodoethoxy) -1H-indol-3-yl] -1- (toluene- 4-Chloro-2- [1-methyl-5-methoxy-6] by following the procedure described in Example 147b except using 0.400 g of 4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine. -(2- (4-Piperidyl-piperidin-1-yl) ethoxy) -1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine is produced To do. 4-chloro-2- [1-methyl-5-methoxy-6- (2- (4-piperidylpiperidin-1-yl) ethoxy) -1H-indol-3-yl] -1- (toluene-4-sulfonyl) ) -1H-pyrrolo [2,3-b] pyridine (0.415 g) is obtained, the properties of which are as follows:

Mass spectrum (CI): m / z = 676 [M + H] ⁺ .

(Example 173)
4-Chloro-2- {5-methoxy-1-methyl-6- [2- (2-pyrrolidin-ethylamino) ethoxy] -1H-indol-3-yl} -1H-pyrrolo [2,3-b] -Pyridine a) 4-chloro-2- {1-methyl-5-methoxy-6- [2- (2-pyrrolidineethylamino) ethoxy] -1H-indol-3-yl} -1- (toluene-4- By following the procedure described in Example 89a except that 0.22 g of sulfonyl) -1H-pyrrolo [2,3-b] pyridine and 1.6 mL of 5N aqueous potassium hydroxide were used, 4-chloro-2- {5- Methoxy-1-methyl-6- [2- (2-pyrrolidin-ethylamino) ethoxy] -1H-indol-3-yl} -1H-pyrrolo [2,3-b] -pyridine is prepared. After purification by flash-pack chromatography (silica, 12/3 / 0.5 volume ratio chloroform / methanol / aqueous ammonia (28%) as eluent) 4-chloro-2- {5-methoxy-1-methyl- 0.095 g of 6- [2- (2-pyrrolidineethylamino) ethoxy] -1H-indol-3-yl} -1H-pyrrolo [2,3-b] pyridine is obtained, the properties of which are as follows: is there.

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value) 1.70 (mt: 4H); 1.70-2.10 (very broad undivided peak: 1 H); 2.45 (mt : 4H); 2.45 to 2.55 (mt: 2H); 2.73 (t, J = 6.5 Hz: 2H); 2.97 (t, J = 6 Hz: 2H); 3.84 (s : 3H); 3.91 (s: 3H); 4.13 (t, J = 6Hz: 2H); 6.72 (large s: 1H); 7.15 (d, J = 5.5Hz: 1H) 7.18 (s: 1 H); 7.45 (s: 1 H); 7.85 (s: 1 H); 8.08 (d, J = 5.5 Hz: 1 H); 12.14 (wide s: 1H). Mass spectrum (CI): m / z = 468 [M + H] ⁺ .

  b) 0.100 mL N- (2-aminoethyl) pyrrolidine and 4-chloro-2- [1-methyl-5-methoxy-6- (2-iodoethoxy) -1H-indol-3-yl] -1- By following the procedure described in Example 147b except using 0.3 g of (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine, 4-chloro-2- {1-methyl-5- Preparation of methoxy-6- [2- (2-pyrrolidine-ethylamino) ethoxy] -1H-indol-3-yl} -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine To do. 4-chloro-2- {5-methoxy-1-methyl-6- [2- (2-pyrrolidine-ethylamino) ethoxy] -1H-indol-3-yl} -1- (toluene-4-sulfonyl)- 0.229 g of 1H-pyrrolo [2,3-b] pyridine is obtained, the properties of which are as follows:

Mass spectrum (CI): m / z = 622 [M + H] ⁺ (reference peak).

(Example 174)
4-chloro-2- {1-methyl-5-methoxy-6- [2- (2piperidineethylamino) ethoxy] -1H-indol-3-yl} -1H-pyrrolo- [2,3-b]- Pyridine a) 4-chloro-2- {1-methyl-5-methoxy-6- [2- (2-piperidineethylamino) ethoxy] -1H-indol-3-yl} -1- (toluene-4-sulfonyl ) -1H-pyrrolo [2,3-b] pyridine and following the procedure described in Example 89a except using 0.240 g of 5N aqueous potassium hydroxide solution and 4-chloro-2- {1-methyl -5-Methoxy-6- [2- (2-piperidineethyl-amino) ethoxy] -1H-indol-3-yl] -1H-pyrrolo [2,3-b] pyridine is prepared. After purification by flash-pack chromatography (silica, 40/5 / 0.5 volume ratio methylene chloride / methanol / aqueous ammonia (28%) as eluent) 4-chloro-2- {1-methyl-5-methoxy 0.092 g of -6- [2- (2-pyrrolidineethylamino) ethoxy] -1H-indol-3-yl} -1H-pyrrolo [2,3-b] pyridine is obtained, the properties of which are as follows: It is.

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value) 1.40 (mt: 2H); 1.51 (mt: 4H); 1.88 (wide undivided peak: 1H); 35 (mt: 4H); 2.39 (t, J = 6.5 Hz: 2H); 2.71 (t, J = 6.5 Hz: 2H); 2.96 (t, J = 5.5 Hz: 2H) 3.83 (s: 3H); 3.91 (s: 3H); 4.13 (t, J = 5.5 Hz: 2H); 6.71 (wide s: 1H); 7.15 (dd) 7.17 (s: 1H); 7.45 (s: 1H); 7.85 (s: 1H); 8.08 (d, J = 5.5Hz: 1H); ); 12.14 (wide s: 1H).

Mass spectrum (CI): m / z = 482 [M + H] ⁺ (reference peak).

  b) 0.135 mL of N- (2-aminoethyl) piperidine and 4-chloro-2- [1-methyl-5-methoxy-6- (2-iodoethoxy) -1H-indol-3-yl] -1- By following the procedure described in Example 147b except using 0.3 g of (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine, 4-chloro-2- {1-methyl-5- Production of methoxy-6- [2- (2-piperidineethyl-amino) ethoxy] -1H-indol-3-yl} -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine To do. 4-chloro-2- {1-methyl-5-methoxy-6- [2- (2-piperidineethyl-amino) ethoxy] -1H-indol-3-yl} -1- (toluene-4-sulfonyl)- 0.246 g of 1H-pyrrolo [2,3-b] -pyridine is obtained, the properties of which are as follows:

Mass spectrum (CI): m / z = 636 [M + H] ⁺ (reference peak).

(Example 175)
2- (5,7-Dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyridine a) 2- (5,7-dimethoxy-1-methyl- 1H- Indol-3-yl) -1H-pyrrolo- [2,3-b] pyridine can be prepared by the following method.

  3.3 mL of 5N aqueous potassium hydroxide solution was added to 2- (5,7-dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo- [2,3 -B] Add to a solution of 0.31 g of pyridine in methanol (20 mL). The mixture is heated at approximately 80 ° C. for about 18 hours. The reaction medium is taken up in 100 ml of an ice + water mixture and extracted three times with 75 ml of ethyl acetate. The combined organic phases are washed with 100 mL water and then with 100 mL saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (13 kPa). The residue is purified by flash chromatography on a silica column [eluent: methylene chloride]. 0.073 g of 2- (5,7-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyridine is obtained in the form of a solid, which has the following properties: Street.

  Melting point: 220 ° C. (Kefler stand).

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value) 3.86 (s: 3H); 3.90 (s: 3H); 4.01 (s: 3H); 6.43 (d 6.71 (d, J = 2 Hz: 1H); 6.99 (d, J = 1.5 Hz: 1H); 7.01 (dd, J = 8 and 5 Hz: 1H); 7.76 (s: 1H); 7.85 (wide d, J = 8 Hz: 1H); 8.11 (dd, J = 5 and 1.5 Hz: 1H); 11.74 (undivided peak: 1H); ).

Mass spectrum (EI): m / z = 307 [M] ⁺ (reference peak); m / z = 292 [M−CH ₃ ] ⁺ .

  b) 2- (5,7-dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine was prepared by the following method. Can be manufactured.

  0.028 g of 60% sodium hydride in oil was added to 2- (5,7-dimethoxy-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3- b] Add in small portions to a solution of 0.26 g of pyridine in dimethylformamide (11.5 mL). The suspension is stirred at about 20 ° C. for about 1 hour and 0.04 mL of methyl iodide is added. After stirring for approximately 18 hours at approximately 20 ° C., the mixture is taken up in 100 mL of an ice + water mixture and extracted three times with 75 mL of ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. 0.3 g of 2- (5,7-dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine is a foam The following characteristics are obtained.

Mass spectrum (ET): m / z = 461 [M] ⁺ (reference peak); m / z = 306 [M−C ₇ H ₇ O ₂ S] ⁺ .

  c) 2-iodo-1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine 2.9 g, 1-tert-butyloxy-carbonyl-5,7-dimethoxy-1H-indole-3 -Follow the procedure described in Example 105e according to the procedure described in Example 105e except that 2.34 g of boronic acid and 19 mL of a saturated aqueous sodium bicarbonate solution in 19 mL of dimethylformamide (63 mL) are added and 0.42 g of tetrakis (triphenylphosphine) palladium is added , 7-dimethoxy-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine can be prepared. After flash chromatography on a silica column [eluent: cyclohexane / ethyl acetate (70/30 volume ratio)], 2- (5,7-dimethoxy-1H-indol-3-yl) -1- (toluene-4- Sulfonyl) -1H-pyrrolo [2,3-b] pyridine 0.26 g is thus obtained in solid form and has the following characteristics.

Silica TLC [eluent: cyclohexane / ethyl acetate (70/30 volume ratio)]
Rf = 0.51.

Mass spectrum (EI): m / z = 447 [M] ⁺ (reference peak); m / z = 292 [M−C ₇ H ₇ O ₂ S] ⁺ .

  The preparation of 2-iodo-1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine is described in patent WO2003000688A1.

  d) 1-tert-Butyloxycarbonyl-5,7-dimethoxy-1H-indole-3-boronic acid can be produced by the following method.

  A solution of 2.2 g of 3-iodo-5,7-dimethoxyindole-1-carboxylic acid tert-butyl ester and 1.8 mL of tributyl borate in tetrahydrofuran (33 mL) was cooled to −100 ° C. and the temperature was approximately −100. While maintaining the temperature at 9.degree. C., 9.82 mL of a hexane solution of 2.5Nn-butyllithium is added dropwise. The cooling bath is removed and when the temperature of the reaction medium reaches about −5 ° C., 2 g of ice are added. After stirring for 1 hour at a temperature close to 20 ° C., the mixture is concentrated to dryness under reduced pressure (13 kPa). The residue is extracted with 200 mL ethyl acetate and washed with 100 mL saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (13 kPa). There are thus obtained 2.34 g of 1-tert-butyloxycarbonyl-5,7-dimethoxy-1H-indole-3-boronic acid in the form of a solid which is used as such in the next step.

  e) The tert-butyl ester of 3-iodo-5,7-dimethoxy-indole-1-carboxylic acid can be prepared by the following method.

  0.94 g of powdered potassium hydroxide is added to a solution of 1.18 g of 5,7-dimethoxy-1H-indole in dimethylformamide (34 mL). To the above mixture, a solution of 1.71 g of iodine sublimated twice in dimethylformamide (34 mL) is added dropwise. The mixture is stirred for 3 hours at a temperature in the region of 20 ° C. and then 0.062 g of 4-dimethylaminopyridine and then a solution of 1.82 g of di-tert-butyl dicarbonate in dimethylformamide (10 mL) are added. After stirring for approximately 18 hours at approximately 20 ° C., the mixture is placed in 89 mL of 0.2% aqueous sodium thiosulfate. The mixture is extracted 3 times with 200 mL of ethyl acetate. The organic phases are combined, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (13 kPa). The residue is purified by flash chromatography on a silica column [eluent: cyclohexane / ethyl acetate (90/10 volume ratio)]. 2.2 g of 3-iodo-5,7-dimethoxyindole-1-carboxylic acid tert-butyl ester are obtained in the form of a solid, the properties of which are as follows:

Silica TLC [eluent: cyclohexane / ethyl acetate (70/30 volume ratio)]
Rf = 0.67.

Mass spectrum (EI): m / z = 403 [M] ⁺ ; m / z = 303 [M−CO ₂ tBu] ⁺ (reference peak).

  5,7-Dimethoxy-1H-indole was produced according to the method described by Milligan et al. (P. J. Milligan and S La Berge, Journal of Medicinal Chemistry, 1970, Vol. 13, No. 6, 1248-1).

(Example 176)
4-chloro-5-fluoro-2- [5,6-dimethoxy-1- (2-morpholin-4-ylethyl) -1H-indol-3-yl] -1H-pyrrolo [2,3-b] pyridine ( A003364503 (P-32416-147-2))
a) 4-Chloro-5-fluoro-2- [1- (2-morpholin-4-ylethyl) -5,6-dimethoxy-1H-indol-3-yl] -1- (toluene-4-sulfonyl)- By following the procedure described in Example 100a, except that 0.260 g of 1H-pyrrolo [2,3-b] pyridine and 0.62 g of 85% potassium hydroxide were used as starting materials, 4-chloro-5-fluoro-2- [5,6-Dimethoxy-1- (2-morpholin-4-ylethyl) -1H-indol-3-yl] -1H-pyrrolo [2,3-b] pyridine can be prepared. After purification by crystallization from 11 cm ^{3 of} acetonitrile, 4-chloro-5-fluoro-2- [5,6-dimethoxy-1- (2-morpholin-4-yl-ethyl) -1H-indol-3-yl] 0.115 g of -1H-pyrrolo [2,3-b] pyridine is obtained, the properties of which are as follows:

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value): 2.47 (partially covered m, 4H); 2.71 (wide t, J = 6.5 Hz, 2H); 3.57 (m, 4H); 3.86 (s, 3H); 3.89 (s, 3H); 4.31 (wide t, J = 6.5 Hz, 2H); 6.74 (d, J = 2.0 Hz, 1H); 7.19 (s, 1H); 7.42 (s, 1H); 7.93 (s, 1H); 8.19 (d, J = 2.0 Hz, 1H); 12.2 (wide s, 1H).

Mass spectrum (EI): m / z = 458 (M) ⁺ (reference peak).

  b) 4-Chloro-5-fluoro-2- [1- (2-iodoethyl) -5,6-dimethoxy-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [ By following the procedure described in Example 100b except that 0.280 g of 2,3-b] pyridine, 0.065 g of potassium carbonate and 0.075 g of morpholine are used as starting materials, 4-chloro-5-fluoro-2- [1 -(2-morpholin-4-ylethyl) -5,6-dimethoxy-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine is prepared. be able to. 4-chloro-5-fluoro-2- [1- (2-morpholin-4-ylethyl) -5,6-dimethoxy-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H- 0.270 g of pyrrolo [2,3-b] pyridine is thus obtained in the form of an orange-red resin, the properties of which are as follows:

-Rf TLC, silica [eluent: cyclohexane / methanol (95/5 volume ratio)] = 0.52.
¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value): 2.27 (s, 3H); 2.45 to 2.55 (covered m, 4H); 2.77 (t , J = 6.5 Hz, 2H); 3.58 (m, 4H); 3.70 (s, 3H); 3.87 (s, 3H); 4.35 (t, J = 6.5 Hz, 2H) 6.77 (s, 1H); 6.84 (s, 1H); 7.17 (s, 1H); 7.20 (wide d, J = 8.5 Hz, 2H); 7.49 (wide) d, J = 8.5 Hz, 2H); 7.60 (s, 1H); 8.48 (d, J = 2.0 Hz, 1H).

  c) 4-Chloro-5-fluoro-2- [1- (2-chloroethyl) -5,6-dimethoxy-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [ By following the procedure described in Example 100c except using 0.260 g of 2,3-b] pyridine and 0.104 g of sodium iodide, 4-chloro-5-fluoro-2- [1- (2- Iodoethyl) -5,6-dimethoxy-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine can be prepared. 4-Chloro-5-fluoro-2- [1- (2-iodoethyl) -5,6-dimethoxy-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2, 3-b] 0.283 g of pyridine is thus obtained in the form of an orange-red resin, the properties of which are as follows:

-Rf TLC, silica [eluent: methylene chloride / ethyl acetate (95/5 volume ratio)] = 0.72;
Mass spectrum (EI): m / z = 653 (M) ⁺ reference peak.

d) 4-Chloro-5-fluoro-2- (5,6-dimethoxy-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine 0 Follow the procedure described in Example 100d except starting with 390 g and a solution of 0.005 g of tetrabutylammonium bromide in 1,2-dichloroethane (30 cm ³ ), 0.343 g of potassium hydroxide and 0.251 g of potassium carbonate. 4-chloro-5-fluoro-2- [1- (2-chloroethyl) -5,6-dimethoxy-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [ 2,3-b] pyridine can be prepared. 4-Chloro-5fluoro-2- [1- (2-chloro-ethyl) -5,6-dimethoxy-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -1H-pyrrolo [2 , 3-b] pyridine 0.260 g is obtained in the form of an orange-red resin, the properties of which are as follows.

-TLC, silica [eluent: methylene chloride / ethyl acetate (95/5 volume ratio)] Rf = 0.56;
Mass spectrum (EI): m / z = 562 (M) ⁺ .

  e) 1- (Toluene-4-sulfonyl) -1H-2-iodo-4-chloro-5-fluoropyrrolo [2,3-b] -pyridine 0.750 g, 1-tert-butyloxycarbonyl-5,6 By following the procedure described in Example 97c except that 0.534 g of dimethoxyindole-3-boronic acid and 0.096 g of tetrakis- (triphenylphosphine) palladium were used as starting materials, 4-chloro-5-fluoro-2- (5,6-dimethoxy-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine can be prepared. 0.390 g of 4-chloro-2- (5,6-dimethoxy-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine was The properties obtained are as follows.

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value): 2.29 (s, 3H); 3.70 (s, 3H); 3.82 (s, 3H); 6.79 (S, 1H); 6.92 (s, 1H); 7.00 (s, 1H); 7.26 (wide d, J = 8.5 Hz, 2H); 7.52 (wide d, J = 8) 7.5 Hz (2H); 7.53 (s, 1H); 8.47 (d, J = 2.0 Hz, 1H); 11.3 (wide s, 1H).

Mass spectrum (EI): m / z = 499 (M) ⁺ .

  1-tert-Butyloxycarbonyl-5,6-dimethoxyindole-3-boronic acid is prepared according to the method described in patent WO03 / 000688A1.

  f) 1- (Toluene-4-sulfonyl) -1H-2-iodo-4-chloro-5-fluoropyrrolo [2,3-b] pyridine can be prepared by the following method.

To a solution of 0.650 g of 1- (toluene-4-sulfonyl) -1H-4-chloro-5-fluoropyrrolo [2,3-b] pyridine in tetrahydrofuran (15 cm ³ ) at about −78 ° C. tert-BuLi 1. 18 cm ³ is added dropwise. The reaction medium is stirred at about −78 ° C. for 30 minutes, then 1.01 g of iodine in tetrahydrofuran (6 cm ³ ) is added dropwise and the temperature is maintained at −78 ° C. for 2 hours. Return temperature to about 0 ° C. After adding 5 cm ^{3 of} saturated aqueous ammonium chloride solution, the reaction mixture is extracted with 80 cm ³ of ethyl acetate, the organic phase is washed 3 times with 20 cm ³ of water, dried over magnesium sulphate and concentrated under reduced pressure (13 kPa). 0.750 g of 1- (toluene-4-sulfonyl) -1H-2-iodo-4-chloro-5-fluoropyrrolo [2,3-b] pyridine is thus obtained in the form of a cream solid, The characteristics are as follows.

-TLC, silica [eluent: methylene chloride] Rf = 0.59;
Mass spectrum (EI): m / z = 451 (M) ⁺ .

  g) 1- (Toluene-4-sulfonyl) -1H-4-chloro-5-fluoropyrrolo [2,3-b] pyridine can be produced by the following method.

4-chloro-5-fluoro-1H-pyrrolo [2,3-b] pyridine 1.30 g, 4-methylbenzenesulfonyl chloride 1.6 g, sodium hydroxide 3.40 g dissolved in water 16 cm ³ and tetrabutyl hydrogen sulfate A mixture of 0.052 g (200 cm ³ ) of ammonium in toluene is stirred at around 20 ° C. for about 24 hours. The mixture is diluted with 500 cm ³ of ethyl acetate and the organic phase is washed 3 times with 200 cm ³ of water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (13 kPa). The residue is purified by flash chromatography on a column of silica [eluent: methylene chloride]. 1.90 g of 4-chloro-5-fluoro-1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine is thus obtained in the form of a powder, the properties of which are as follows: It is.

Melting point: melting at 125 ° C. (Kefler block);
¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value): 2.36 (s, 3 H); 6.93 (d, J = 3.0 Hz, 1 H); 7.44 (wide d , J = 8.0 Hz, 2H); 7.99 (wide d, J = 8.0 Hz, 2H); 8.12 (d, J = 3.0 Hz, 1H); 8.52 (d, J = 2) .5Hz, 1H);
Mass spectrum (EI): m / z = 324 (M) ⁺ .

  h) 4-Chloro-5-fluoro-1H-pyrrolo [2,3-b] pyridine can be prepared by the following method.

A solution of 1.7 g of 5-fluoro-1H-pyrrolo [2,3-b] pyridine-7-oxide in phosphorus oxychloride (10 cm ³ ) is maintained at the reflux temperature of POCl ₃ for 8 hours. After the POCl ₃ is distilled off under reduced pressure, the residue is treated with 50 g of ice and sodium bicarbonate is added to bring the pH of the resulting solution to around 8-9. The aqueous phase is extracted 5 times with 80 cm ³ of ethyl acetate. The combined organic phases are dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (13 kPa). 1.3 g of 4-chloro-5-fluoro-1H-pyrrolo [2,3-b] pyridine is thus obtained in solid form, the properties of which are as follows:

-Rf TLC, silica [eluent: methylene chloride / methanol (98/2 volume ratio)] = 0.19;
¹ H NMR spectrum (400 MHz, (CD ₃ ) ₂ SO d6, δ ppm value) 6.56 (m, 1H); 7.70 (m, 1H); 8.35 (d, J = 2.5 Hz, 1H 12.15 (wide m, 1H);
Mass spectrum (EI): m / z = 170 (M) ⁺ .

  i) 5-Fluoro-1H-pyrrolo [2,3-b] pyridine 7-oxide can be prepared by the following method.

6.22 g of 3-chloroperbenzoic acid is added to a solution of 2.7 g of 5-fluoro-1H-pyrrolo [2,3-b] pyridine in dimethoxyethane (70 cm ³ ). The reaction medium is stirred at around 20 ° C. for 1 hour 30 minutes. After adding 2 g of potassium hydroxide in methanol (20 cm ³ ), the mixture is extracted 5 times with 100 cm ³ of ethyl acetate. The organic phase is washed twice with 15 cm ³ of saturated ammonium chloride solution, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (13 kPa). The residue is purified by flash chromatography on a column of silica [eluent: methylene chloride / methanol (95/5 volume ratio)] to give 3.6 g of a solid, which is washed with 25 cm ³ of diethyl oxide, Dehydrate and dry. The residue was purified by flash chromatography on a column of silica [eluent: cyclohexane / ethyl acetate (50/50 volume ratio)] to give 5-fluoro-1H-pyrrolo [2,3-b] pyridine 7-oxide. 1.70 g is obtained in the form of a powder, the properties of which are as follows:

Melting point: melting at 178 ° C. (Kefler block);
IR spectrum: KBr 3128; 3085; 2919; 2863; 2734; 2629; 2406; 1588; 1507; 1349; 1129; 1077; 990; 804; 723; 670 and 466 cm ⁻¹ .

  j) 5-Fluoro-1H-pyrrolo [2,3-b] pyridine can be produced by the following method.

Maintain a mixture of 3.80 g 5-fluoro-3-trimethylsilanyl-ethynylpyrid-2-ylamine and 3.40 g potassium tert-butoxide in 1-methylpyrrolidin-2-one (100 cm ³ ) at around 130 ° C. for about 4 hours To do. After cooling to a temperature around 20 ° C., the mixture is poured into 1000 cm ³ of a saturated aqueous sodium chloride solution and extracted five times with 250 cm ³ of diethyl oxide. The organic phases are combined, washed 5 times with 100 cm ³ of a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (13 kPa). 2.35 g of 5-fluoro-1H-pyrrolo [2,3-b] pyridine is obtained in the form of a solid, the properties of which are as follows:

Melting point: melting at 110 ° C. (Kefler block);
Mass spectrum (EI): m / z = 136 (M) ⁺ reference peak m / z = 109 (M-HCN) ⁺ .

  k) 5-Fluoro-3-trimethylsilanylethynylpyrid-2-yl-amine can be prepared by the following method.

12.47 cm ^{3 of} ethynyltrimethylsilane, 2.24 g of copper iodide, 2.74 g of lithium chloride, 41.33 cm ^{3 of} triethylamine and 2.15 g of [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) chloride Add 14 g of 5-fluoro-3-iodo-pyrid-2-ylamine degassed with argon to a solution of dimethylformamide (440 cm ³ ). The resulting solution is maintained at a temperature around 55 ° C. for about 5 hours. After cooling to a temperature close to 20 ° C., the mixture is concentrated under reduced pressure (13 kPa). The residue is taken up in 300 cm ³ of water and extracted three times with 100 cm ³ of ethyl acetate. The combined organic phases are washed 3 times with 100 cm ³ of water, dried over magnesium sulphate, filtered and concentrated under reduced pressure (13 kPa). After flash chromatography on a column of silica (eluent; methylene chloride), 7.91 g of 5-fluoro-3-trimethylsilanylethynylpyrid-2-ylamine are thus obtained in solid form and its properties Is as follows.

Melting point: melting at 65 ° C. (Kefler block);
Mass spectrum (EI): m / z = 208 (M) ⁺ ; m / z = 193 (M-CH ₃ ) ⁺ reference peak.

  l) 5-Fluoro-3-iodo-pyrid-2-ylamine can be prepared by the following method.

A mixture of 9.9 g of 5-fluoropyrid-3-ylamine and 21.85 g of N-iodosuccinimide in acetic acid (400 cm ³ ) is stirred at a temperature around 70 ° C. for about 6 hours. After concentrating to dryness under reduced pressure (13 kPa), the residue is taken up in 250 cm ³ of water. The pH is adjusted to about 8 by adding sodium bicarbonate. The aqueous phase is extracted 5 times with 150 cm ³ of methylene chloride. The combined organic phases are washed 3 times with 100 cm ³ of water and 5 times with 50 cm ³ of 10% aqueous sodium thiosulfate solution, dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure (13 kPa). After flash chromatography on a silica column (eluent: methylene chloride), 11 g of 5-fluoro-3-iodo-pyrid-2-ylamine are thus obtained in solid form, the properties of which are as follows: is there.

Melting point: Melting at 76 ° C. (Kefler block);
^-1 H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value) 5.98 (wide s, 2H); 7.93-7.98 (m, 2H).

Mass spectrum (EI): m / z = 238 (M) ⁺ .

(Example 177)
2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylamine (A003346712 (P-32441-067-1))
a) 2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylamine can be prepared by the following method. .

2- (1-Methyl) -5,6-dimethoxy-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H degassed with 1.05 cm ³ of tetrabutylammonium fluoride with argon -Pyrrolo [2,3-b] pyrid-4-ylamine is added to a solution of 0.1 g of tetrahydrofuran (10 cm ³ ). The resulting solution is refluxed for about 24 hours. After cooling to a temperature close to 20 ° C., the mixture is concentrated under reduced pressure (13 kPa). The residue is taken up in 50 cm ³ of saturated sodium hydrogen carbonate solution and extracted 3 times with 50 cm ³ of ethyl acetate and then 3 times with 100 cm ³ of methylene chloride. The combined organic phases are washed 3 times with 100 cm ³ of water, dried over magnesium sulphate, filtered and concentrated under reduced pressure (13 kPa). After flash chromatography on a column of silica [eluent: methylene chloride / methanol (90/10 volume ratio)], 2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H— 0.015 g of pyrrolo [2,3-b] pyrid-4-ylamine is thus obtained in the form of a white solid, the properties of which are as follows:

¹ H NMR spectrum (400 MHz, (CD ₃ ) ₂ SO d6, δ ppm value) 3.79 (s, 3H); 3.87 (s, 3H); 3.89 (s, 3H); 6.07 ( 6.13 (d, J = 5.0 Hz, 1H); 6.82 (wide s, 1H); 7.09 (s, 1H); 7.43 (s, 1H); 7 .63 (s, 1H); 7.67 (d, J = 5.0 Hz, 1H); 11.2 (wide s, 1H).

Mass spectrum (EI): m / z = 322 (M) ⁺ .

  b) 2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylamine Can be produced by the following method.

A 2N aqueous hydrochloric acid solution (5.5 cm ³⁾ was added to benzhydrylidene- [2- (1-methyl) -5,6-dimethoxy-1H-indol-3-yl) -1- (toluene-4sulfonyl) -1H-pyrrolo [ 2,3-b] pyrid-4-yl] amine is added to a solution of 0.7 g of tetrahydrofuran (20 cm ³ ). The resulting solution is stirred at about 20 ° C. for about 3 hours. The mixture is concentrated under reduced pressure (13 kPa). The residue is taken up in 50 cm ³ of saturated sodium hydrogen carbonate solution and extracted 3 times with 50 cm ³ of ethyl acetate and then 3 times with 25 cm ³ of methylene chloride. The combined organic phases are washed 3 times with 50 cm ³ of water, dried over magnesium sulphate, filtered and concentrated under reduced pressure (13 kPa). After flash chromatography on a silica column [eluent: methylene chloride / methanol (98/2 volume ratio)], 2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1- 0.31 g of (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylamine is thus obtained in the form of a pale pink solid, the properties of which are as follows:

-TLC, silica [eluent: methylene chloride / methanol (98/2 volume ratio)] Rf = 0.125;
Mass spectrum (ET): m / z = 476 (M) ⁺ .

  c) Benzhydrylidene- [2- (1-methyl) -5,6-dimethoxy-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] Pyrid-4-yl] amine can be prepared by the following method.

4-chloro obtained by degassing 1.7 g of cesium carbonate, 0.4 g of (R)-(+)-2,2-bis (diphenylphosphino) -1,1′-binaphthyl and 0.377 g of benzophenone imine with argon A solution of 0.8 g of 2- (5,6-dimethoxy-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine in toluene (80 cm ³ ) Add to. The resulting solution is stirred at about 20 ° C. for about 15 minutes and 0.144 g of palladium acetate is added. The mixture is refluxed for 4 hours, cooled to about 20 ° C. and then filtered through a sintered funnel filled with celite. The cake is washed 3 times with 20 cm ³ of methylene chloride and the filtrate is concentrated under reduced pressure (13 kPa). After flash chromatography on a column of silica [eluent: cyclohexane / ethyl acetate (50/50 volume ratio)], benzhydrylidene- [2- (1-methyl) -5,6-dimethoxy-1H-indole-3 -Yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-yl] amine is thus obtained in the form of a yellow solid, whose properties are It is as follows.

^-1 H NMR spectrum (400 MHz, (CD ₃ ) ₂ SO d6, δ ppm value): 2.31 (s, 3H); 3.72 (s, 3H); 3.82 (s, 3H); 3.86 (S, 3H); 6.49 (s, 1H); 6.61 (d, J = 5.0 Hz, 1H); 6.88 (s, 1H); 7.08 (s, 1H); 20 (wide d, 8.5 Hz, 2H); 7.39 (wide d, J = 8.5 Hz, 2H); 7.41 (s, 1H); 7.05 to 7.75 (very wide m, 10H); 8.02 (d, J = 5.0 Hz, 1H).

Mass spectrum (IC): m / z = 641 (M + H) ⁺ .

  4-Chloro-2- (5,6-dimethoxy-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine is described in Example 97b. Obtained according to the method of

(Example 178)
Cyclohexyl [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] amine (A003341949 (P-31916-162) 1)))
a) Cyclohexyl [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] amine is produced by the following method. can do.

1 cm ³ of a tetrahydrofuran solution of 1M tetrabutylammonium fluoride (TBAF) was added to cyclohexyl [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1- ( Toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] amine is added to a solution of 0.14 g of tetrahydrofuran (10 cm ³ ). The reaction medium is stirred at this same temperature for 15 hours and then refluxed for 24 hours. After cooling, the reaction medium is evaporated to dryness under reduced pressure. Add 4 cm ³ of water. The resulting solid is filtered off through a sinter funnel and washed with water and then ethyl ether. The solid obtained is taken up in water and the medium is made basic at pH 10 with 0.1N sodium hydroxide. The product is extracted 5 times with methylene chloride. The organic phases are combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. 0.029 g of cyclohexyl [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] amine is thus obtained. Its characteristics are as follows.

^-1 H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value): 1.05-1.28 (m, 5H); 1.48-1.76 (m, 3H); 1.85 2.03 (m, 2H); 3.17-3.42 (covered m, 1H); 3.80 (s, 3H); 3.85 (s, 3H); 3.88 (s, 3H) 4.05 (wide s, 2H); 6.82 (d, J = 2.0 Hz, 1H); 7.02 (d, J = 5.0 Hz, 1H); 7.11 (s, 1H) 7.45 (s, 1H); 7.75 (s, 1H); 8.03 (d, J = 5.0 Hz, 1H); 11.65 (wide s, 1H).

Mass spectrum (EI): m / z = 418 (M) ⁺ ; m / z = 321 (M−C ₆ H ₁₁ N) ⁺ reference peak.

  b) Cyclohexyl [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4- [Ilmethyl] amine can be prepared by the following method.

2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridi-4-carboxaldehyde 16 g and 0.4 g of sodium sulfate are added to a solution of 0.24 g of cyclohexylamine in methylene chloride (5 cm ³ ) at a temperature around 20 ° C. under an inert atmosphere of argon. Stirring is maintained for 48 hours at room temperature. Add 5 cm ^{3 of} methanol and 0.023 g of sodium borohydride. The reaction medium is stirred for 6 hours at the same temperature. The reaction medium is concentrated under reduced pressure. The residue obtained is taken up in 10 cm ³ of methylene chloride. The precipitate formed is filtered off and the filtrate is concentrated under reduced pressure and purified by column flash chromatography (SiO ₂ , methylene chloride / methanol as eluent, 98/02 volume ratio). Fractions containing product were combined, concentrated under reduced pressure to dryness, and cyclohexyl [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4 0.143 g of (sulfonyl) pyrrolo [2,3-b] pyrid-4-ylmethyl] amine is obtained.

-Mass spectrum (EI): m / z = 572 (M) ⁺ ; m / z = 417 (M-C ₇ H ₇ SO ₂ ) ⁺ reference peak; m / z = 320 (m / z = 417-C ₆ H ₁₁ N) ⁺ .

  c) 2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridi-4-carboxaldehyde Can be manufactured by the following method.

At a temperature close to 20 ° C., 16.5 cm ³ of 5N hydrochloric acid was added to 2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -4- (1,3-dioxolan) -2-yl. -1- (Toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine is added to a solution of 4.4 g of tetrahydrofuran (100 cm ³ ). The reaction medium is stirred at this same temperature for 24 hours. Addition of water 30 cm ³ and methylene chloride 30 cm ^3. After the phases are separated by settling, the organic phase is dried over magnesium sulfate, filtered, concentrated under reduced pressure and purified on a silica column eluting with a 50/50 volume ratio of cyclohexane and ethyl acetate. Fractions containing product were combined, concentrated under reduced pressure to dryness, and 2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) ) -1H-pyrrolo [2,3-b] pyridi-4-carboxaldehyde 2.6 g was obtained, the properties of which are as follows:

Mass spectrum (EI): m / z = 489 (M) ⁺ ; m / z = 334 (M−C ₇ H ₇ SO ₂ ) ⁺ reference peak.

  d) 2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -4- (1,3-dioxolan) -2-yl-1- (toluene-4-sulfonyl) -1H- Pyrrolo [2,3-b] pyridine can be produced by the following method.

0.462 g of a 60% sodium hydride suspension in oil was added to 2- (5,6-dimethoxy-1H-indol-3-yl) -4- () at a temperature around 20 ° C. under an inert atmosphere of argon. 1,3-Dioxolan) -2-yl-1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine is added to a solution of 5 g of dehydrated dimethylformamide (DMF) (185 cm ³ ). The reaction medium is stirred for 45 minutes at the same temperature. 0.719 cm ³ of methyl iodide is added dropwise. The reaction medium is stirred at this same temperature for 20 hours. Add 200 cm ^{3 of} water and 100 cm ³ of ethyl acetate. After the phases are separated by settling, the organic phase is dried over magnesium sulfate, filtered, concentrated under reduced pressure and purified on a column of silica eluting with a 98/02 volume ratio of methylene chloride and methanol mixture. Fractions containing the product were combined, concentrated under reduced pressure to dryness, and 2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -4- (1,3-dioxolane). ) -2-yl-1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine (4.42 g) was obtained, and the characteristics thereof were as follows.

- Mass Spectrum ^{(EI): m / z =} 533 (M) +; m / z = 378 (M-C 7 H 7 SO 2) + base peak.

  e) 2- (5,6-Dimethoxy-1H-indol-3-yl) -4- (1,3-dioxolan) -2-yl-1- (toluene-4-sulfonyl) -1H-pyrrolo [2, 3-b] pyridine can be produced by the following method.

41 cm ^{3 of a} saturated sodium bicarbonate solution and 0.611 g of tetrakis (triphenylphosphine) palladium at a temperature close to 20 ° C. under an inert atmosphere of argon, 4- (1,3-dioxolan) -2-yl-2- 6.2 g iodo-1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine, 135 cm ³ dehydrated DMF and 1-tert-butyloxycarbonyl-5,6-dimethoxyindole-3-boronic acid Add to 7.42 g of solution. The reaction medium is heated at 130 ° C. for 3 hours. After cooling, the reaction medium is concentrated under reduced pressure. The oil obtained is taken up in 80 cm ^{3 of} water and 100 cm ³ of ethyl acetate. After the phases are separated by settling, the organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (SiO ₂ , 50/50 volume ratio ethyl acetate / cyclohexane, argon as eluent). Fractions containing product are concentrated under reduced pressure. 2- (5,6-dimethoxy-1H-indol-3-yl) -4- (1,3-dioxolane) -2-yl-1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3- b] 5 g of pyridine are thus obtained, the properties of which are as follows:

- Mass Spectrum ^{(EI): m / z =} 519 (M) +; m / z = 364 (M-C 7 H 7 SO 2) + base peak.

  1-t-Butyloxycarbonyl-5,6-dimethoxyindole-3-boronic acid is produced according to the method described in patent WO03 / 000688A1.

  f) 4- (1,3-Dioxolane) -2-yl-2-iodo-1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine is produced by the following method. Can do.

4- (1,3-Dioxolan) -2-yl-1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine at a temperature around −78 ° C. under an inert atmosphere of argon in dry tetrahydrofuran (100 cm ³⁾ solution of 5g, added dropwise n-BuLi (2.5M hexane solution) 5.81cm ^3. The reaction medium is stirred at this same temperature for 25 minutes and a solution of 7.37 g of iodine in tetrahydrofuran (50 cm ³ ) is added dropwise. The reaction medium is stirred at −78 ° C. for 15 minutes. Remove the cooling bath. After stirring for 2 hours, the temperature rises to room temperature. The reaction medium is stirred at room temperature for 20 hours. Adding water 15cm ³ and ethyl acetate 15cm ^3. After the phases are separated by settling, the organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (SiO ₂ , methylene chloride, argon as eluent). Fractions containing product are concentrated under reduced pressure. 6.28 g of 4- (1,3-dioxolane) -2-yl-2-iodo-1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine are thus obtained, which The characteristics are as follows.

Mass spectrum (ES): m / z = 471 (M + H) ⁺ reference peak.

  g) 4- (1,3-Dioxolane) -2-yl-1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine can be prepared by the following method.

Under an inert atmosphere of argon, 1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine-4-carboxaldehyde in a toluene (250 cm ³ ) solution of 5.8 g of ethylene glycol 2.15 cm ³ and 0.735 g of para-toluenesulfonic acid are added. The reaction medium is heated at 120 ° C. for 3 hours. After cooling, water is added 50 cm ³ of ethyl acetate 50 cm ^3. After the phases are separated by settling, the organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue is triturated in ethyl ether. The resulting solid is filtered off and washed with 20 cm ³ of ethyl ether. 5.3 g of 4- (1,3-dioxolan) -2-yl-1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine are thus obtained, the properties of which are It is as follows.

- Mass Spectrum ^{(EI): m / z =} 344 (M) +; m / z = 237 (M-C 7 H 7 SO 2) + base _{peak; m / z = 91 (C} 7 H 7) +.

  h) 1- (Toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine-4-carboxaldehyde can be produced by the following method.

In a toluene (400 cm ³ ) solution of 10 g of 1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine-4-carbonitrile at a temperature around −30 ° C. under an inert atmosphere of argon. 50.5 cm ³ of diisobutylaluminum hydride (DIBAH) as a 20 wt% toluene solution (1 M) is added dropwise. After stirring for 40 minutes at this same temperature, the cooling bath is removed. The temperature is raised to 20 ° C. The reaction medium is stirred at a temperature in the region of 20 ° C. for 1 hour. The reaction medium is cooled to 4 ° C. Add 1N hydrochloric acid dropwise to pH 6. The precipitate formed is filtered off and washed with 50 cm ^{3 of} water and 280 cm ³ of ethyl acetate. After separation of the filtrate by settling, the organic phase is dried over sodium sulfate, filtered, concentrated under reduced pressure and purified by column flash chromatography (SiO ₂ , methylene chloride, Ar as eluent). Fractions containing product are concentrated under reduced pressure. 4.3 g of 1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine-4-carboxaldehyde are thus obtained, the properties of which are as follows:

- Mass Spectrum ^{(EI): m / z =} 300 (M) +; m / z = 236 (M-SO 2) +; m / z = 91; (C 7 H 7 +) base peak.

  i) 1- (Toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine-4-carbonitrile can be prepared by the following method.

Zinc cyanide was added to a solution of 10 g of 4-chloro-1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine in N, N-dimethylacetamide (200 cm ³ ) under an inert atmosphere of argon. Add 6.9 g and 1.07 g of zinc powder. After stirring for 45 minutes at a temperature in the region of 20 ° C., 2.4 g of [1,1′-bis (diphenylphosphino) -ferrocene] palladium (II) (PdCl ₂ , dppf) are added. The reaction medium is heated at a temperature close to 140 ° C. for 90 minutes. After cooling, the reaction medium is filtered through celite and washed with methylene chloride. Add water 150cm ³ to the filtrate. After the phases are separated by settling, the organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure. Flash column chromatography (SiO _2, cyclohexane / ethyl acetate 75/25 by volume as the eluent, Ar) after purification by 1- (toluene-4-sulfonyl)-1H-pyrrolo [2,3-b] pyridine -4 -8.57 g of carbonitrile are obtained, the properties of which are as follows:

- Mass Spectrum ^{(EI): m / z =} 297 (M) +; m / z = 233 (M-SO 2) +; m / z = 91 (C 7 H 7) + base peak.

  The compound 4-chloro-1- (toluene-4-sulfonyl) -1H-pyrrolo- [2,3-b] pyridine is prepared according to the method described in patent WO03 / 000688A1.

(Example 179)
[2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] (4-trifluoromethylsulfanylbenzyl) amine ( A003364149 (P-32520-098-1))
a) [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] (4-trifluoromethylsulfanylbenzyl) The amine can be produced by the following method.

[2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] at temperatures around 20 ° C. the pyrid-4-ylmethyl] (4-trifluoromethylsulfanyl-benzyl) amine 0.04g of methanol (2 cm ³⁾ solution was added 5N potassium hydroxide 0.265 cm ^3. The reaction medium is refluxed for 6 hours. After cooling, the reaction medium is concentrated under reduced pressure. The residue obtained is taken up in 4 cm ³ of water. The resulting solid was filtered off through a sintered funnel, washed twice with ³ cm ³ of water, dried in vacuo and [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H— 0.030 g of pyrrolo [2,3-b] pyrid-4-ylmethyl] (4-trifluoromethylsulfanylbenzyl) amine was obtained, and its characteristics are as follows.

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value) 2.85 to 3.00 (wide m, 1H); 3.80 (s, 3H); 3.85 (s, 3H) 3.87 (s, 3H); 3.78-3.90 (covered m, 2H); 4.06 (wide s, 2H); 6.79 (wide s, 1H); 7.07 ( d, J = 5.0 Hz, 1 H); 7.11 (s, 1 H); 7.45 (s, 1 H); 7.58 (wide d, J = 8.5 Hz, 2 H); 7.68 (wide) d, J = 8.5 Hz, 2H); 7.76 (s, 1H); 8.07 (d, J = 5.0 Hz, 1H); 11.7 (wide s, 1H).

Mass spectrum (EI): m / z = 526 (M) ⁺ ; m / z = 321 (M−C ₈ H ₆ SNF ₃ ) ⁺ reference peak.

b) 2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridi-4-carboxaldehyde According to the method described in Example 178b, using 0.065 g and 0.08 cm ³ of 4-trifluoromethylsulfanylbenzylamine instead of cyclohexylamine used in Example 178b, [2- (5,6- Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] (4-trifluoromethylsulfanylbenzyl) Amines can be produced. Flash - Pack chromatography (SiO _2, methylene chloride / methanol 98/02 by volume as eluant) after purification by, [2- (5,6-dimethoxy-1-methyl -1H- indol-3-yl) -1 0.044 g of-(toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] (4-trifluoromethylsulfanylbenzyl) amine is obtained, the properties of which are as follows: is there.

- Mass Spectrum _{^{(EI): m / z =}} 680 (M) +; m / z = 525 (M-C 7 H 7 SO 2) +; m / z = 320 (m / z = 525-C 8 H 6 SNF ₃ ) ⁺ reference peak.

(Example 180)
Phenyl [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] amine (A003390480 (P-32520-140-) 4))
a) [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl)-] used in Example 179a according to the method described in Example 179a Phenyl [2- (5,6-dimethoxy-1-methyl-1H-indole-3) instead of 1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] (4-trifluoromethylsulfanylbenzyl) amine -Yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] amine 0.120 g and 5N potassium hydroxide 0.95 cm ³ as raw materials -(5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] amine is prepared. 0.010 g of phenyl [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] amine was obtained, The characteristics are as follows.

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value) 3.81 (s, 3H); 3.87 (s, 3H); 3.89 (s, 3H); 4.61 ( d, J = 6.0 Hz, 2H); 6.43 (t, J = 6.0 Hz, 1H); 6.49 (wide t, J = 7.5 Hz, 1H); 6.61 (wide d, J = 7.5 Hz, 2H); 6.91 (d, J = 2.0 Hz, 1H); 6.96 to 7.05 (m, 3H); 7.11 (s, 1H); 7.47 (s) 1H); 7.76 (s, 1H); 8.02 (d, J = 5.0 Hz, 1H); 11.7 (wide s, 1H).

Mass spectrum: (ES); m / z = 413; (M + H) ⁺ reference peak.

b) 2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3 according to the method described in Example 178b -B] Phenyl [2- (5,6-dimethoxy-1-methyl-1H) using 0.137 g of pyridi-4-carboxaldehyde and 0.037 cm ³ of aniline instead of cyclohexylamine used in Example 178b as raw materials. -Indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] amine is prepared. Flash - Pack chromatography after purification by (SiO _2, methylene chloride / methanol 98/02 by volume as eluant), phenyl [2- (5,6-dimethoxy-1-methyl -1H- indol-3-yl) - 0.122 g of 1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-yl-methyl] amine is obtained, the properties of which are as follows:

Mass spectrum (ES): m / z = 567 (M + H) ⁺ .

(Example 181)
Benzyl [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] amine (A003389983 (P-32520-141- 1))
a) [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl)-] used in Example 179a according to the method described in Example 179a Benzyl [2- (5,6-dimethoxy-1-methyl-1H-indole) instead of 1H-pyrrolo [2,3-b] pyrid-4-yl-methyl] (4-trifluoromethylsulfanylbenzyl) amine Starting from 0.070 g of -3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] -amine and 0.54 cm ³ of 5N potassium hydroxide, Benzyl [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] amine is prepared. 0.038 g of benzyl [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] amine was obtained, The characteristics are as follows.

^-1 H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value) 2.60-2.80 (wide m, 1H); 3.78 (wide s, 2H); 3.81 (s, 3H 3.85 (s, 3H); 3.87 (s, 3H); 4.03 (wide s, 2H); 6.79 (d, J = 2.0 Hz, 1H); 7.06 (d , J = 5.0 Hz, 1H); 7.11 (s, 1H); 7.23 (wide t, J = 7.5 Hz, 1H); 7.31 (wide t, J = 7.5 Hz, 2H) 7.41 (wide d, J = 7.5 Hz, 2H); 7.43 (s, 1H); 7.75 (s, 1H); 8.06 (d, J = 5.0 Hz, 1H); 11.65 (wide s, 1H).

Mass spectrum (EI): m / z = 426 (M) ⁺ ; m / z = 321 (M−C ₈ H ₆ SNF ₃ ) ⁺ reference peak.

b) 2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3 according to the method described in Example 178b -B] -pyrid-4-carbonaldehyde 0.1 g and benzylamine 0.045 cm ³ instead of cyclohexylamine used in Example 178b as starting materials, benzyl [2- (5,6-dimethoxy-1-methyl) -1H-Indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] amine is prepared. Flash - Pack chromatography after purification by (SiO _2, methylene chloride / methanol 98/02 by volume as eluant), benzyl [2- (5,6-dimethoxy-1-methyl -1H- indol-3-yl) - 0.071 g of 1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-yl-methyl] amine is obtained, the properties of which are as follows:

Mass spectrum (ES): m / z = 581 (M + H) ⁺ ; m / z = 474 (M + H—C ₇ H ₉ N) ⁺ reference peak.

(Example 182)
[2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] phenylethylamine (A003391552 (P-32520-158- 1))
a) [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl)-] used in Example 179a according to the method described in Example 179a [2- (5,6-dimethoxy-1-methyl-1H-indole-] instead of 1H-pyrrolo- [2,3-b] pyrid-4-ylmethyl] (4-trifluoromethylsulfanyl-benzyl) amine Starting from 0.16 g of 3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] -phenylethylamine and 1.2 cm ³ of 5N potassium hydroxide, [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] phenylethylamine is produced. The 0.038 g of [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] -phenylethylamine was obtained, which The characteristics are as follows.

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value) 2.10 to 2.25 (broad m, 1H); 2.75 to 2.86 (m, 4H); 3.81 ( 3.87 (s, 6H); 4.07 (wide s, 2H); 6.80 (wide d, J = 2.0 Hz, 1H); 6.99 (d, J = 5. 7.12 (s, 1H); 7.12-7.30 (m, 5H); 7.46 (s, 1H); 7.74 (s, 1H); 8.03 (d) , J = 5.0 Hz, 1H); 11.65 (wide s, 1H).

Mass spectrum (EI): m / z = 440 (M) ⁺ ; m / z = 320 (M−C ₈ H ₁₀ N) ⁺ reference peak.

b) 2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3 according to the method described in Example 178b -B] -pyridi-4-carboxaldehyde 0.15 g and phenylethylamine 0.192 cm ³ instead of cyclohexylamine used in Example 178b as starting materials [2- (5,6-dimethoxy-1-methyl- 1H-Indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] -phenylethylamine is prepared. Flash - after purification by packed chromatography (SiO _2, methylene chloride / methanol 99/01 as eluant, then methylene chloride / methanol 98.5 / 1.5 by volume), [2- (5,6-dimethoxy - 0.17 g of 1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] -phenylethylamine was obtained, which The characteristics are as follows.

Mass spectrum (ES): m / z = 595 (M + H) ⁺ reference peak; m / z = 474 (M + H—C ₈ H ₁₁ N) ⁺ .

(Example 183)
[2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] phenylpropylamine (A003390226 (P-32520-144) 1))
a) [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl)-] used in Example 179a according to the method described in Example 179a [2- (5,6-dimethoxy-1-methyl-1H-indole-] instead of 1H-pyrrolo- [2,3-b] pyrid-4-ylmethyl] (4-trifluoromethylsulfanyl-benzyl) amine Starting from 0.115 g of 3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] -phenylpropylamine and 0.85 cm ³ of 5N potassium hydroxide, [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] phenylpropylamine Manufacturing. 0.072 g of [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] -phenylpropylamine was obtained, which The characteristics are as follows.

^-1 H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value) 1.78 (m, 2H); 2.15 to 2.40 (wide m, 1H); 2.58 (wide t, J = 6.5 Hz, 2H); 2.64 (wide t, J = 7.5 Hz, 2H); 3.78 (s, 3H); 3.81 (s, 3H); 3.86 (s, 3H) 4.02 (wide s, 2H); 6.82 (wide s, 1H); 7.00 (d, J = 5.0 Hz, 1H); 7.09 (s, 1H); 7.06-7 .28 (m, 5H); 7.45 (s, 1H); 7.75 (s, 1H); 8.03 (d, J = 5.0 Hz, 1H); 11.65 (wide s, 1H) .

Mass spectrum (ES): m / z = 455 (M + H) ⁺ ; m / z = 320 (M + H—C ₉ H ₁₃ N) ⁺ reference peak.

b) 2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3 according to the method described in Example 178b -B] -pyrid-4-carbonaldehyde 0.15 g and phenylpropylamine 0.218 cm ³ instead of cyclohexylamine used in Example 178b as starting materials [2- (5,6-dimethoxy-1-methyl- 1H-Indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] phenyl-propylamine is prepared. Flash - Pack chromatography (SiO _2, methylene chloride / methanol 98/02 by volume as eluant) after purification by, [2- (5,6-dimethoxy-1-methyl -1H- indol-3-yl) -1 0.120 g of-(toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] -phenylpropylamine is obtained, the properties of which are as follows:

- Mass Spectrum ^{_{(EI): m / z =}} 608 (M) +; m / z = 453 (M-C 7 H 7 SO 2) +; m / z = 320 (m / z = 453-C 9 H 11 N) ⁺ Reference peak.

(Example 184)
[2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethylthiophen-2-ylmethylamine (A003391639 (P -32520-162-1))
a) [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl)-] used in Example 179a according to the method described in Example 179a [2- (5,6-dimethoxy-1-methyl-1H-indole-3-] instead of 1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] (4-trifluoromethylsulfanylbenzyl) amine Yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] thiophen-2-ylmethylamine 0.15 g and 5N potassium hydroxide 0.85 cm ³ [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] thiophen-2-yl Methylamine is produced. [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] -thiophen-2-ylmethylamine 0.056 g Is obtained, and its characteristics are as follows.

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value) 2.87 (wide m, 1H); 3.81 (s, 3H); 3.87 (s, 6H); 3.95 (M, 2H); 4.04 (m, 2H); 6.81 (d, J = 2.0 Hz, 1H); 6.95 to 7.01 (m, 2H); 7.03 (d, J = 5.0 Hz, 1H); 7.11 (s, 1H); 7.39 (dd, J = 2.0 and 5.0 Hz, 1H); 7.47 (s, 1H); 7.77 (s) 1H); 8.07 (d, J = 5.0 Hz, 1H); 11.7 (wide s, 1H).

Mass spectrum (ES): m / z = 433 (M + H) ⁺ ; m / z = 337 (M + H—C ₅ H ₄ S) ⁺ reference peak; m / z = 320 (M + H—C ₅ H ₇ NS) ⁺ .

b) 2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo- [2, following the method described in Example 178b. [3- (5,6-dimethoxy-], starting from 0.15 g of 3-b] pyrid-4-carboxaldehyde and 0.158 cm ³ of thiophene-2-methylamine instead of cyclohexylamine used in Example 178b. 1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] -thiophen-2-ylmethylamine is prepared. . Flash - after purification by packed chromatography (SiO _2, methylene chloride / methanol 99/01 as then methylene chloride / methanol 98.5 / 1.5 by volume as the eluent), [2- (5,6-dimethoxy - 1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-yl-methyl] thiophen-2-ylmethylamine 11 g are obtained, the characteristics of which are as follows:

Mass spectrum (ES): m / z = 587 (M + H) ⁺ reference peak; m / z = 474 (M + H—C ₅ H ₇ NS) ⁺ .

(Example 185)
[2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] thiophen-2-ylethylamine (A003391615 (P- 32520-160-1))
a) [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl)-] used in Example 179a according to the method described in Example 179a [2- (5,6-dimethoxy-1-methyl-1H-indole-3-] instead of 1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] (4-trifluoromethylsulfanylbenzyl) amine Yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] -thiophen-2-ylethylamine 0.15 g and 5N potassium hydroxide 1.12 cm ³ As [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] thiophen-2-y Ruethylamine is produced. 0.082 g of [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] -thiophen-2-ylethylamine The properties obtained are as follows.

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value): 2.25 to 2.38 (wide m, 1H); 2.86 (wide t, J = 6.5 Hz, 2H); 3.00 (t, J = 6.5 Hz, 2H); 3.80 (s, 3H); 3.86 (s, 6H); 4.07 (wide s, 2H); 6.80 (wide d, 6.87 (wide d, J = 3.5 Hz, 1H); 6.91 (dd, J = 3.5 and 5.0 Hz, 1H); 7.01 (d, J = 2.0 Hz, 1H); 7.10 (s, 1H); 7.27 (wide d, J = 5.0 Hz, 1H); 7.47 (s, 1H); 7.76 (s, 1H) 8.04 (d, J = 5.0 Hz, 1H); 11.65 (wide s, 1H).

Mass spectrum (ES): m / z = 447 (M + H) ⁺ ; m / z = 320 (M + H—C ₆ H ₉ NS) ⁺ reference peak.

b) 2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo- [2, following the method described in Example 178b. [3- (5,6-dimethoxy-1] using 0.15 g of 3-b] pyrid-4-carbonaldehyde and 0.179 cm ³ of thiophen-2-ethylamine instead of cyclohexylamine used in Example 178b -Methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] -thiophen-2-ylethylamine is prepared. Flash - after purification by packed chromatography (SiO _2, methylene chloride / methanol 99/01 as then methylene chloride / methanol 98.5 / 1.5 by volume as the eluent), [2- (5,6-dimethoxy - 0.15 g of 1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] thiophen-2-ylethylamine is obtained. Its characteristics are as follows.

Mass spectrum (ES): m / z = 601 (M + H) ⁺ ; m / z = 474 (MH—C ₆ H ₉ NS) ⁺ reference peak.

(Example 186)
[2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] (2-methoxyethyl) amine (A003391652 (P -32520-163-1))
a) [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl)-] used in Example 179a according to the method described in Example 179a [2- (5,6-dimethoxy-1-methyl-1H-indole-] instead of 1H-pyrrolo- [2,3-b] pyrid-4-ylmethyl] (4-trifluoromethylsulfanyl-benzyl) amine 3-Iyl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl]-(2-methoxyethyl) amine 0.12 g and 5N potassium hydroxide 0.99 cm ³ as a raw material, [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] (2-methoxyethyl) I) Amine is produced. [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl]-(2-methoxyethyl) amine 0.081 g Is obtained, and its characteristics are as follows.

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value): 2.13 to 2.29 (wide m, 1H); 2.73 (wide t, J = 6.5 Hz, 2H); 3.25 (s, 3H); 3.45 (t, J = 6.5 Hz, 2H); 3.81 (s, 3H); 3.87 (s, 3H); 3.89 (s, 3H) 4.04 (wide s, 2H); 6.81 (wide d, J = 2.0 Hz, 1H); 7.01 (d, J = 5.0 Hz, 1H); 7.11 (s, 1H); 7.47 (s, 1H); 7.74 (s, 1H); 8.04 (d, J = 5.0 Hz, 1H); 11.65 (wide s, 1H).

Mass spectrum (ES): m / z = 395 (M + H) ⁺ ; m / z = 320 (M + H—C ₃ H ₉ NO) ⁺ reference peak.

b) 2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3 according to the method described in Example 178b -B] -pyridi-4-carboxaldehyde 0.15 g and 2-methoxyethyl-amine 0.134 cm ³ instead of cyclohexylamine used in Example 178b as starting materials [2- (5,6-dimethoxy- 1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl]-(2-methoxyethyl) amine is prepared. . Flash - after purification by packed chromatography (SiO _2, methylene chloride / methanol 99/01 as then methylene chloride / methanol 98.5 / 1.5 by volume as the eluent), [2- (5,6-dimethoxy - 1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl]-(2-methoxyethyl) amine 0.11 g Is obtained, and its characteristics are as follows.

Mass spectrum (ES): m / z = 549 (M + H) ⁺ reference peak; m / z = 474 (M + H—C ₃ H ₉ NO) ⁺ .

(Example 187)
4-({[2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] amino} methyl) -phenylamine (A003393788 (P-33047-027-1))
4-({[2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] amino} methyl) phenylamine Can be produced by the following method.

At a temperature around 20 ° C., 4-[({[2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl ] Amino} methyl) phenyl] carbamic acid tert-butyl ester To a solution of 0.07 g of dioxane (1.5 cm ³ ) and DMF (0.5 cm ³ ) is added 1.6 cm ³ of hydrochloric acid (4N dioxane solution). The reaction medium is stirred at room temperature for 24 hours. The reaction medium is concentrated under reduced pressure. The residue obtained is taken up in 4 cm ³ of water and neutralized with triethylamine. Add 4 cm ³ of methylene chloride. After the phases are separated by settling, the organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue obtained is taken up in 5 cm ³ of water. The resulting solid was filtered off through a sinter funnel, washed twice with ³ cm ³ of water and dried in vacuo to give 4-({[2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl. ) -1H-pyrrolo- [2,3-b] pyrid-4-ylmethyl] amino} methyl) phenylamine, 0.036 g, is obtained, the properties of which are as follows.

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value) 3.60-3.78 (wide m, 2H); 3.81 (s, 3H); 3.87 (s, 6H) 4.02-4.13 (wide m, 2H); 4.85-5.02 (wide m, 2H); 6.53 (wide d, J = 8.5 Hz, 2H); 6.80 (wide) 7.01-7.10 (m, 3H); 7.12 (s, 1H); 7.45 (s, 1H); 7.77 (s, 1H); 8.09 (d) , J = 5.0 Hz, 1H); 11.7 (wide m, 1H).

Mass spectrum (EI): m / z = 441 (M) ⁺ ; m / z = 321 (M−C ₇ H ₈ N ₂ ) ⁺ reference peak.

(Example 188)
4-[({[2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] amino] methyl) phenyl] Carbamic acid tert-butyl ester (A003393158 (P-33047-016-1))
a) [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl)-] used in Example 179a according to the method described in Example 179a 4-[({[2- (5,6-dimethoxy-1-methyl-1H instead of 1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] (4-trifluoromethylsulfanylbenzyl) amine -Indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] amino} methyl) phenyl] -carbamic acid tert-butyl ester 0.16 g and 5N potassium 1.04 cm ³ as the raw material hydroxide, 4 - [({[2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo [2, 3-b] pyrid-4-ylmethyl] amino} methyl) phenyl] -carbamic acid tert-butyl ester is prepared. 4-[({[2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] -amino} methyl) phenyl There are obtained 0.093 g of carbamic acid tert-butyl ester, the properties of which are as follows:

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value) 1.48 (s, 9H); 2.60 (wide m, 1H); 3.69 (m, 2H); 3.81 (S, 3H); 3.86 (s, 3H); 3.87 (s, 3H); 4.00 (m, 2H); 6.78 (wide d, J = 2.0 Hz, 1H); 7 .05 (d, J = 5.0 Hz, 1H); 7.11 (s, 1H); 7.25 (wide d, J = 8.5 Hz, 2H); 7.40 (wide d, J = 8. 10.42 (s, 1H); 7.74 (s, 1H); 8.06 (d, J = 5.0 Hz, 1H); 9.22 (wide s, 1H); 65 (wide s, 1H).

Mass spectrum (ES): m / z = 542 (M + H) ⁺ reference peak; m / z = 337 (M + H—C ₁₂ H ₁₅ NO ₂ ) ⁺ .

b) 2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3 according to the method described in Example 178b -B] 0.15 g of pyridi-4-carboxaldehyde and 0.340 cm ³ of (4- (aminomethyl) phenyl) carbamic acid tert-butyl ester instead of cyclohexylamine used in Example 178b as starting materials, [({[2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4- Yl-methyl] amino} methyl) phenyl] carbamic acid tert-butyl ester is prepared. Flash - after purification by packed chromatography (SiO _2, methylene chloride / methanol 99/01 as then methylene chloride / methanol 98.5 / 1.5 by volume as the eluent), 4 - [({[2- (5 , 6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] -pyrid-4-ylmethyl] amino} methyl) phenyl 0.16 g of carbamic acid tert-butyl ester is obtained, the properties of which are as follows:

Mass spectrum (ES): m / z = 696 (M + H) ⁺ ; m / z = 337 (M + H—C ₁₂ H ₁₅ NO ₂ ) ⁺ reference peak.

(Example 189)
[2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] (4-trifluoromethyl-sulfanylphenyl) amine (A003403451 (P-33047-052-1))
a) [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl)-] used in Example 179a according to the method described in Example 179a [2- (5,6-dimethoxy-1-methyl-1H-indole-] instead of 1H-pyrrolo [2,3-b] pyrid-4-yl-methyl] (4-trifluoromethylsulfanylbenzyl) amine 3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] -pyrid-4-ylmethyl] (4-trifluoromethylsulfanylphenyl) amine 0.08 g and 5N potassium hydroxide Using 0.53 cm ³ as a starting material, [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl L] (4-trifluoromethylsulfanylphenyl) amine. Phenyl [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] (4-trifluoromethyl-sulfanylphenyl) 0.068 g of amine is obtained, the properties of which are as follows:

^-1 H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value) 3.80 (s, 3 H); 3.86 (s, 3 H); 3.88 (s, 3 H); 4.67 ( d, J = 6.0 Hz, 2H); 6.70 (wide d, J = 8.5 Hz, 2H); 6.90 (wide s, 1H); 6.97 (d, J = 5.0 Hz, 1H) 7.10 (s, 1H); 7.23 (wide t, J = 6.0 Hz, 1H); 7.32 (wide d, J = 8.5 Hz, 2H); 7.47 (s, 1H) ); 7.77 (s, 1H); 8.04 (d, J = 5.0 Hz, 1H); 11.75 (wide m, 1H).

Mass spectrum (EI): m / z = 512 (M) ⁺ ; m / z = 320 (M−C ₇ H ₅ SNF ₃ ) ⁺ reference peak.

b) 2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3 according to the method described in Example 178b -B] By using 0.15 g of pyridi-4-carboxaldehyde and 0.219 cm ³ of 4- (trifluoromethylsulfanyl) aniline instead of cyclohexylamine used in Example 178b as a starting material, [2- (5,6- Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl]-(4-trifluoromethylsulfanylphenyl) ) Producing amines. Flash - Pack chromatography (SiO _2, methylene chloride / methanol 98/02 by volume as eluant) after purification by, [2- (5,6-dimethoxy-1-methyl -1H- indol-3-yl) -1 0.084 g of-(toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] (4-trifluoromethylsulfanylphenyl) amine is obtained, the properties of which are as follows: is there.

-Mass spectrum (ES): m / z = 667 (M + H) ⁺ reference peak.

(Example 190)
Cyclopropyl [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] amine (A003403453 (P-33047-058) -1))
a) [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl)-] used in Example 179a according to the method described in Example 179a Cyclopropyl [2- (5,6-dimethoxy-1-methyl-1H-) instead of 1H-pyrrolo [2,3-b] pyrid-4-yl-methyl] (4-trifluoromethylsulfanylbenzyl) amine Starting from 0.06 g of indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] -amine and 0.5 cm ³ of 5N potassium hydroxide Cyclopropyl [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] amine is prepared. . 0.034 g of cyclopropyl [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] amine was obtained, which The characteristics are as follows.

^-1 H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value) 0.30 to 0.42 (m, 4H); 2.13 (m, 1H); 2.72 to 2.86 (wide) m, 1H); 3.80 (s, 3H); 3.86 (s, 3H); 3.88 (s, 3H); 4.06 (wide s, 2H); 6.81 (d, J = 7.00 (d, J = 5.0 Hz, 1H); 7.11 (s, 1H); 7.47 (s, 1H); 7.75 (s, 1H); 8 .04 (d, J = 5.0 Hz, 1H); 11.65 (wide m, 1H).

Mass spectrum (EI): m / z = 376 (M) ⁺ ; m / z = 320 (M−C ₃ H ₆ N) ⁺ reference peak.

b) 2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3 according to the method described in Example 178b -B] -pyridi-4-carboxaldehyde 0.15 g and cyclopropylamine 0.107 cm ³ instead of cyclohexylamine used in Example 178b as starting materials, cyclopropyl [2- (5,6-dimethoxy-1 -Methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] amine is prepared. Flash - Pack chromatography (SiO _2, methylene chloride / methanol 98/02 by volume as eluant) after purification by cyclopropyl [2- (5,6-dimethoxy-1-methyl -1H- indol-3-yl) 0.075 g of -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] -pyrid-4-ylmethyl] amine is obtained, the properties of which are as follows.
- Mass Spectrum ^{(EI): m / z =} 530 (M) +; m / z = 375 (M-C 7 H 7 SO 2) + base peak; m / z = 320 (m / z = 375-C 3 H ₅ ^N) +.

(Example 191)
[2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] (4-morpholin-4-ylphenyl) amine (A003403814 (P-33047-056-2))
a) [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl)-] used in Example 179a according to the method described in Example 179a [2- (5,6-dimethoxy-1-methyl-1H-indole-3-] instead of 1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] (4-trifluoromethylsulfanylbenzyl) amine Yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] (4-morpholin-4-ylphenyl) amine 0.16 g and 5N potassium hydroxide. [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] (4-mol) using 08 cm ³ as a raw material Holin-4-ylphenyl) -amine is prepared. [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl]-(4-morpholin-4-ylphenyl) 0.068 g of amine is obtained, the properties of which are as follows:

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value) 2.83 (m, 4H); 3.67 (m, 4H); 3.80 (s, 3H); 3.85 ( 3.89 (s, 3H); 4.58 (d, J = 6.0 Hz, 2H); 6.02 (t, J = 6.0 Hz, 1H); 6.56 (wide d) , J = 8.5 Hz, 2H); 6.70 (wide d, J = 8.5 Hz, 2H); 6.91 (d, J = 2.0 Hz, 1H); 6.98 (d, J = 5) 10.10 (s, 1H); 7.48 (s, 1H); 7.75 (s, 1H); 8.01 (d, J = 5.0 Hz, 1H); 7 (wide m, 1H).

Mass spectrum (EI): m / z = 497 (M) ⁺ ; m / z = 320 (M−C ₁₀ H ₁₃ N ₂ O) ⁺ reference peak.

b) 2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo- [2, following the method described in Example 178b. [2- (5,6- Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl]-(4-morpholin-4-yl (Phenyl) amine is produced. Flash - Pack chromatography (SiO _2, methylene chloride / methanol 98/02 by volume as eluant) after purification by, [2- (5,6-dimethoxy-1-methyl -1H- indol-3-yl) -1 0.164 g of-(toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] -pyrid-4-ylmethyl] (4-morpholin-4-ylphenyl) amine is obtained, which has the following properties Street.

-Mass spectrum (EI): m / z = 651 (M) ⁺ ; m / z = 496 (M-C ₇ H ₇ SO ₂ ) ⁺ ; m / z = 177 (C ₁₀ H ₁₃ N ₂ O) ⁺ reference peak.

(Example 192)
[2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] (2-methyl-2H-pyrazole-3- Yl) amine (A003405576 (P-33047-062-1))
a) [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl)-] used in Example 179a according to the method described in Example 179a [2- (5,6-dimethoxy-1-methyl-1H-indole-] instead of 1H-pyrrolo- [2,3-b] pyrid-4-ylmethyl] (4-trifluoromethylsulfanyl-benzyl) amine 3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] -pyrid-4-ylmethyl] (2-methyl-2H-pyrazol-3-yl) amine trifluoroacetic acid Using 0.08 g of salt and 0.62 cm ³ of 5N potassium hydroxide as raw materials, [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] Pi [Lid-4-ylmethyl] (2-methyl-2H-pyrazol-3-yl) amine is prepared. Flash - pack after purification by chromatography (SiO _2, methylene chloride / methanol 98/02 by volume as eluent), [2- (5,6-dimethoxy-1-methyl -1H- indol-3-yl) -1H 0.024 g of pyrrolo [2,3-b] pyrid-4-ylmethyl] (2-methyl-2H-pyrazol-3-yl) amine is obtained, the properties of which are as follows:

^-1 H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value) 3.60 (s, 3 H); 3.81 (s, 3 H); 3.86 (s, 3 H); 3.88 ( s, 3H); 4.53 (d, J = 6.0 Hz, 2H); 5.28 (d, J = 2.0 Hz, 1H); 6.24 (wide t, J = 6.0 Hz, 1H) 6.90 (d, J = 2.0 Hz, 1H); 7.00 (d, J = 2.0 Hz, 1H); 7.02 (d, J = 5.0 Hz, 1H); 7.11 ( 7.47 (s, 1H); 7.77 (s, 1H); 8.04 (d, J = 5.0 Hz, 1H); 11.7 (wide s, 1H).

Mass spectrum (EI): m / z = 416 (M) ⁺ ; m / z = 320 (M−C ₄ H ₆ N ₃ ) ⁺ reference peak.

b) 2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3 according to the method described in Example 178b -B] Starting from 0.15 g of pyridi-4-carboxaldehyde and 0.149 g of 1-methyl-1H-pyrazol-5-ylamine instead of cyclohexylamine used in Example 178b, [2- (5,6 -Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl]-(2-methyl-2H- Pyrazol-3-yl) amine is prepared. Flash-pack chromatography (SiO ₂ , methylene chloride / methanol 98/02 volume ratio as eluent) followed by chromatography on a column of Kromasil C8 10 μm (eluent: water / acetonitrile / TFA 70/30/0 .1 volume ratio) followed by [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo- [2,3 -B] Pyrid-4-ylmethyl] (2-methyl-2H-pyrazol-3-yl) amine trifluoroacetate 0.08 g is obtained, the properties of which are as follows.

- Mass Spectrum ^{(EI): m / z =} 570 (M) +; m / z = 415 (M-C 7 H 7 SO 2) + base peak; m / z = 320 (m / z = 415-C 4 H ₅ N ₃₎ ^+.

(Example 193)
[2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] (1-methylpiperid-4-yl) -amine (A003440113 (P-33047-137-1))
a) [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl)-] used in Example 179a according to the method described in Example 179a [2- (5,6-dimethoxy-1-methyl-1H-indole-3) instead of 1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] (4-trifluoro-methylsulfanylbenzyl) amine -Yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-yl-methyl] (1-methylpiperid-4-yl) amine 0.07 g and 5N potassium hydroxide Using 0.48 cm ³ as a raw material, [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] (1- Mechi Lupiperid-4-yl) -amine is prepared. [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] (1-methylpiperidi-4-yl) amine 0 0.042 g is obtained, the properties of which are as follows:

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value) 1.34 (m, 2H); 1.85 (m, 4H); 2.11 (s, 3H); 2.42 ( m, 1H); 2.69 (m, 2H); 3.81 (s, 3H); 3.87 (s, 3H); 3.88 (s, 3H); 4.05 (s, 2H); 6.81 (d, J = 2.0 Hz, 1H); 7.02 (d, J = 5.0 Hz, 1H); 7.11 (s, 1H); 7.44 (s, 1H); 75 (s, 1H); 8.03 (d, J = 5.0 Hz, 1H); 11.65 (wide s, 1H).

Mass spectrum (ES: m / z = 434 (M + H) ⁺ ; m / z = 218 (M + 2H) ²⁺ / 2; reference peak.

b) 2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo- [2, following the method described in Example 178b. 3-b] Pyridi-4-carboxaldehyde 0.15 g and 1-methyl-4-aminopiperidine 0.175 g instead of cyclohexylamine used in Example 178b as starting materials [2- (5,6-dimethoxy -1-Methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl]-(1-methylpiperid-4-yl) Produces an amine. Flash - Pack chromatography (SiO _2, methylene chloride / methanol 90/10 by volume as eluant) after purification by, [2- (5,6-dimethoxy-1-methyl -1H- indol-3-yl) -1 0.070 g of-(toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] -pyrid-4-ylmethyl] (1-methylpiperidi-4-yl) amine is obtained, the properties of which are as follows: It is.

Mass spectrum (IC): m / z = 588 (M + H) ⁺ reference peak.

(Example 194)
(2,4-dimethoxybenzyl) [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] -amine ( A003408775 (P-32989-041-1))
a) [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl)-] used in Example 179a according to the method described in Example 179a 1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] (4-trifluoromethyl-sulfanylbenzyl) amine instead of (2,4-dimethoxybenzyl) [2- (5,6-dimethoxy-1 -Methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo- [2,3-b] pyrid-4-ylmethyl] amine 0.05 g and 5N potassium hydroxide Using 36 cm ³ as a raw material, (2,4-dimethoxybenzyl) [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyridy -4-ylmethyl] amine is produced. (2,4-Dimethoxybenzyl)-[2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] amine 0 0.03 g is obtained, the properties of which are as follows:

^-1 H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value) 3.67 (wide s, 2H); 3.72 (s, 3H); 3.73 (s, 3H); 3.81 (S, 3H); 3.85 (s, 3H); 3.87 (s, 3H); 4.04 (wide s, 2H); 6.49 (dd, J = 2.5 and 8.5 Hz, 6.52 (d, J = 2.5 Hz, 1H); 6.76 (d, J = 2.0 Hz, 1H); 7.06 (d, J = 5.0 Hz, 1H); 11. (s, 1H); 7.28 (d, J = 8.5 Hz, 1H); 7.42 (s, 1H); 7.75 (s, 1H); 8.06 (d, J = 5. 0 Hz, 1H); 11.65 (wide s, 1H).

-Mass spectrum (ES): m / z = 487 (M + H) ⁺ reference peak.

b) 2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo- [2, following the method described in Example 178b. 3-b] Pyridi-4-carboxaldehyde (2 g) and 2,4-dimethoxybenzylamine (3.39 g) instead of cyclohexylamine used in Example 178b as starting materials, (2,4-dimethoxybenzyl) [2- ( 5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] -pyrid-4-ylmethyl] amine is prepared. . Flash - after purification by packed chromatography (SiO _2, methylene chloride / methanol 98/02 by volume as eluant), (2,4-dimethoxybenzyl) [2- (5,6-dimethoxy-1-methyl -1H- 1.2 g of indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] amine are obtained, the properties of which are as follows: .

Mass spectrum (ES): m / z = 641 (M + H) ⁺ ; m / z = 486 (M + H—C ₇ H ₇ SO ₂ ) ⁺ .

(Example 195)
[2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] (4-piperidi-1-ylphenyl)- Amines (A003425429 (P-333047-107-1))
a) [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl)-] used in Example 179a according to the method described in Example 179a [2- (5,6-dimethoxy-1-methyl-1H-indole-3) instead of 1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] (4-trifluoro-methylsulfanylbenzyl) amine -Yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-yl-methyl] (4-piperidi-1-ylphenyl) amine 0.09 g and 5N hydroxylation Starting from 0.55 cm ³ of potassium, [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] (4 -Pi Peridi-1-ylphenyl) -amine is prepared. [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] (4-piperidi-1-ylphenyl) amine 0.016 g is obtained, the properties of which are as follows:

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value): 1.45 (m, 2H); 1.59 (m, 4H); 2.83 (m, 4H); 3.82 (S, 3H); 3.88 (s, 3H); 3.90 (s, 3H); 4.57 (wide m, 2H); 6.00 (wide m, 1H); 6.55 (wide d) 6.70 (wide d, J = 8.5 Hz, 2H); 6.92 (wide s, 1H); 7.00 (wide d, J = 5.0 Hz, 1H) 7.11 (wide s, 1H); 7.49 (wide s, 1H); 7.78 (wide s, 1H); 8.02 (wide d, J = 5.0 Hz, 1H); 7 (wide s, 1H).

Mass spectrum (EI): m / z = 495 (M) ⁺ ; m / z = 320 (M−C ₁₁ H ₁₅ N ₂ ) ⁺ ; m / z = 175 (C ₁₁ H ₁₅ N ₂ ⁺ ) Reference peak .

b) 2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo- [2, following the method described in Example 178b. 3-b] Pyridi-4-carboxaldehyde 0.15 g and (4-piperidin-1-ylphenyl) amine 0.27 g instead of cyclohexylamine used in Example 178b were used as starting materials. 6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl]-(4-piperidi-1 -Ylphenyl) amine is produced. Flash - Pack chromatography (SiO _2, methylene chloride / methanol 99/01 by volume as eluant) after purification by, [2- (5,6-dimethoxy-1-methyl -1H- indol-3-yl) -1 0.12 g of-(toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] -pyrid-4-ylmethyl] (4-piperidin-1-ylphenyl) amine is [2- (5,6- Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] -pyrid-4-ylmethyl] (4-piperidin-1-yl) Obtained as a mixture (60/40) with phenyl) imine. This mixture is dissolved in 7 cm ³ of ethanol at a temperature around 20 ° C. Add 0.016 g of sodium borohydride. The reaction medium is stirred at room temperature for 24 hours. The reaction medium is concentrated under reduced pressure. The residue obtained is taken up in 3 cm ^{3 of} water and 4 cm ³ of methylene chloride. After the phases are separated by settling, the organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. Flash - after purification by packed chromatography (SiO _2, methylene chloride / methanol 99.5 / 0.5 by volume as eluant), [2- (5,6-dimethoxy-1-methyl -1H- indol-3 Yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-yl-methyl] (4-piperidin-1-ylphenyl) amine The characteristics are as follows.

Mass spectrum (EI): m / z = 649 (M) ⁺ ; m / z = 175 (C ₁₁ H ₁₅ N ₂ ⁺ ) reference peak.

(Example 196)
[2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] [4- (2,6-dimethylmorpholine- 4-ylphenyl) amine (A003425496 (P-333047-113-1))
a) [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl)-] used in Example 179a according to the method described in Example 179a [2- (5,6-dimethoxy-1-methyl-1H-indole-] instead of 1H-pyrrolo [2,3-b] pyrid-4-yl-methyl] (4-trifluoromethylsulfanylbenzyl) amine 3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] -pyrid-4-ylmethyl] [4- (2,6-dimethylmorpholin-4-ylphenyl) -amine Using 0.08 g and 1 cm ³ of 5N potassium hydroxide as raw materials, [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4 -Ile Methyl] [4- (2,6-dimethylmorpholin-4-ylphenyl) amine is prepared. [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo- [2,3-b] pyrid-4-ylmethyl] [4- (2,6-dimethylmorpholine 0.017 g of -4-yl-phenyl) amine is obtained, the properties of which are as follows:

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value) 1.09 (d, J = 7.0 Hz, 6H); 2.08 (m, 2H); 3.21 (m, 2H) 3.63 (m, 2H); 3.80 (s, 3H); 3.87 (s, 3H); 3.89 (s, 3H); 4.56 (wide d, J = 6.0 Hz) 6.00 (wide t, J = 6.0 Hz, 1H); 6.55 (wide d, J = 8.5 Hz, 2H); 6.69 (wide d, J = 8.5 Hz, 2H) 6.91 (wide s, 1H); 6.98 (d, J = 5.0 Hz, 1H); 7.11 (s, 1H); 7.47 (s, 1H); 7.75 (s) 1H); 8.01 (d, J = 5.0 Hz, 1H); 11.65 (wide s, 1H).

Mass spectrum (EI): m / z = 525 (M) ⁺ ; m / z = 320 (M−C ₁₂ H ₁₇ N ₂ O) ⁺ reference peak; m / z = 206 (C ₁₂ H ₁₈ N ₂ O ) ⁺ .

b) 2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3- according to the method described in Example 178b b] Using 0.15 g of pyridi-4-carboxaldehyde and 0.316 g of 4- (2,6-dimethylmorpholin-4-ylphenyl) amine instead of cyclohexylamine used in Example 178b as raw materials, (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl]-[4- (2,6-Dimethylmorpholin-4-ylphenyl) amine is prepared. Flash - Pack chromatography (SiO _2, methylene chloride / methanol 99/01 by volume as eluant) after purification by, [2- (5,6-dimethoxy-1-methyl -1H- indol-3-yl) -1 0.1 g of-(toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] [4- (2,6-dimethylmorpholin-4-ylphenyl) amine is [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl]-[4- Obtained as a mixture (50/50) with (2,6-dimethylmorpholin-4-ylphenyl) imine. This mixture is dissolved in 7 cm ³ of ethanol at a temperature around 20 ° C. Add 0.016 g of sodium borohydride. The reaction medium is stirred at room temperature for 24 hours. The reaction medium is concentrated under reduced pressure. The residue obtained is taken up in 3 cm ^{3 of} water and 4 cm ³ of methylene chloride. After the phases are separated by settling, the organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. Flash - after purification by packed chromatography (SiO _2, methylene chloride / Detanoru as eluent (dethanol) 99/01 by volume), [2- (5,6-dimethoxy-1-methyl -1H- indol-3-yl 0.08 g of -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] [4- (2,6-dimethylmorpholin-4-ylphenyl) amine is obtained. Its characteristics are as follows.

Mass spectrum (EI): m / z = 679 (M) ⁺ ; m / z = 206 (C ₁₂ H ₁₈ N ₂ O ⁺ ); m / z = 120 (C ₇ H ₈ N ₂ ⁺ ) Reference peak.

(Example 197)
[2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-yl] methanol (A003377259 (P-32520-113-1) ))
a) [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl)-] used in Example 179a according to the method described in Example 179a [2- (5,6-dimethoxy-1-methyl-1H-indole-3-] instead of 1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] (4-trifluoromethylsulfanylbenzyl) amine Yl) -1- (toluene-4sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-yl] methanol 0.08 g and 5N potassium hydroxide 0.55 cm ³ as raw materials [2- (5 , 6-Dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-yl] methanol. 0.036 g of [2- (5,6dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-yl] methanol was obtained, the properties of which were It is as follows.

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value) 3.72 to 3.97 (wide m, 9H); 4.85 (wide s, 2H); 5.32 (wide s, 6.75 (wide s, 1H); 7.03 (wide s, 1H); 7.11 (wide s, 1H); 7.45 (wide s, 1H); 7.75 (wide s, 1H); 8.08 (wide s, 1H); 11.65 (wide s, 1H).

-Mass spectrum (EI): m / z = 337 (M) ⁺ reference peak.

  b) [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-yl Methanol can be produced by the following method.

0.054 mg sodium borohydride at a temperature around 20 ° C. 2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] Pyridi-4-carboxaldehyde is added to a solution of 0.47 g in methanol (10 cm ³ ). The reaction medium is stirred at room temperature for 4 hours. The reaction medium is concentrated under reduced pressure. The residue obtained is taken up in 10 cm ^{3 of} water and 20 cm ³ of ethyl acetate. After the phases are separated by settling, the organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. Flash - Pack chromatography (SiO _2, methylene chloride / methanol 98/02 by volume as eluant) after purification by, [2- (5,6-dimethoxy-1-methyl -1H- indol-3-yl) -1 0.45 g of-(toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-yl] methanol is obtained, the properties of which are as follows:

Mass spectrum (ES): m / z = 492 (M + H) ⁺ reference peak.

(Example 198)
1 ′-[2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] [1,4 ′] bipiperidyl: (A003408597 (P-33047-074-1))
a) [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl)-] used in Example 179a according to the method described in Example 179a 1 '-[2- (5,6-dimethoxy-1-methyl-1H- in place of 1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] (4-trifluoromethyl-sulfanylbenzyl) amine Indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-yl-methyl] [1,4 '] bipiperidyl 0.025 g and 5N potassium hydroxide Using 0.17 cm ³ as a raw material, 1 ′-[2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] [1,4 ' ] Bipiperidyl is produced. 1 '-[2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl]-[1,4'] bipiperidyl 0.01 g is obtained, the properties of which are as follows:

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value) 1.30 to 1.56 (m, 8H); 1.71 (m, 2H); 2.01 (m, 2H); 2.17 (m, 1H); 2.42 (m, 4H); 2.94 (m, 2H); 3.78 (s, 2H); 3.80 (s, 3H); 3.86 (s) 3.88 (s, 3H); 6.87 (d, J = 2.0 Hz, 1H); 6.93 (d, J = 5.0 Hz, 1H); 7.11 (s, 1H) 7.41 (s, 1H); 7.76 (s, 1H); 8.04 (d, J = 5.0 Hz, 1H); 11.70 (wide s, 1H).

Mass spectrum (EI): m / z = 487 (M) ⁺ ; m / z = 320 (M−C ₁₀ H ₁₉ N ₂ ) ⁺ reference peak.

  b) 1 '-[2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridy- 4-ylmethyl] [1,4 ′] bipiperidyl can be prepared by the following method.

0.003 g of sodium hydride is added to a solution of 0.008 g of 4-piperidinopiperidine in THF (0.5 cm ³ ) at a temperature around 20 ° C. The reaction medium is stirred at room temperature for 20 minutes. Methanesulfonic acid 2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-yl Add 0.04 g of methyl ester. The reaction medium is heated at 60 ° C. for 3 hours. After cooling, the reaction medium is concentrated under reduced pressure. The residue obtained is taken up in 2 cm ^{3 of} water and 3 cm ³ of ethyl acetate. After the phases are separated by settling, the organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. Flash - after purification by packed chromatography (SiO _2, methylene chloride / methanol 90/10 by volume as eluant), 1 '- [2- (5,6-dimethoxy-1-methyl -1H- indol-3-yl ) -1- (Toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] [1,4 ′] bipiperidyl, 0.026 g, which has the following characteristics: is there.

Mass spectrum (ES): m / z = 642 (M + H) ⁺ ; m / z = 244 (M + H—C ₇ H ₇ SO ₂ + H) ²⁺ / 2 reference peak.

  c) Methanesulfonic acid 2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridi-4 -The ylmethyl ester can be manufactured by the following method.

0.064 g of pyridine and 0.092 g of methanesulfonic anhydride were mixed with [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4] at a temperature around −10 ° C. -Sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-yl] methanol 0.13 g is added to a solution of methylene chloride (5 cm ³ ). The reaction medium is stirred at this same temperature for 1 hour and then at room temperature for 24 hours. Add ice and 15 cm ³ of methylene chloride. After the phases are separated by settling, the organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. Flash - after purification by packed chromatography (SiO _2, methylene chloride / methanol 98/02 by volume as eluant), methane - sulphonic acid 2- (5,6-dimethoxy-1-methyl -1H- indol-3-yl ) -1- (Toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl ester is obtained with the following characteristics.

Mass spectrum (ES): m / z = 570 (M + H) ⁺ reference peak.

(Example 199)
[2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] diethylamine (A003416358 (P-33047-091-1 ))
a) [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl)-] used in Example 179a according to the method described in Example 179a [2- (5,6-dimethoxy-1-methyl-1H-indole-] instead of 1H-pyrrolo [2,3-b] pyrid-4-yl-methyl] (4-trifluoromethylsulfanylbenzyl) amine Starting from 0.060 g of 3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] diethylamine and 0.44 cm ³ of 5N potassium hydroxide, [2 -(5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] diethylamine is prepared. 0.034 g of [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] diethylamine is obtained, its properties Is as follows.

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value): 1.06 (t, J = 7.0 Hz, 6H); 2.53 (partially covered m, 4H); 3.81 (s, 3H); 3.83 (s, 2H); 3.87 (s, 6H); 6.86 (d, J = 2.0 Hz, 1H); 6.99 (d, J = 7.11 (s, 1H); 7.41 (s, 1H); 7.74 (s, 1H); 8.03 (d, J = 5.0 Hz, 1H); 11 .65 (wide s, 1H).

Mass spectrum (EI): m / z = 392 M ⁺ ; m / z = 321 (M−C ₄ H ₉ N) ⁺ reference peak.

  b) [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl ] -Diethylamine can be produced by the following method.

Thionyl chloride 0.022 cm ³ was treated with [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo at a temperature around 20 ° C. [2,3-b] pyrid-4-yl] methanol 0.15 g is added to a methylene chloride (3 cm ³ ) solution followed by 2 drops of DMF. The reaction medium is stirred at this same temperature for 4 hours.

Then, acetonitrile 8 cm ^3, diethylamine 0.160Cm ^3, is added potassium carbonate 0.211g and sodium iodide 0.1 g. The reaction medium is heated at 50 ° C. for 24 hours. After cooling, the reaction medium is filtered through a sintered funnel and the filtrate is concentrated under reduced pressure. The residue obtained is taken up in 3 cm ^{3 of} water and 4 cm ³ of ethyl acetate. After the phases are separated by settling, the organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. Flash - Pack chromatography after purification by (SiO _2, methylene chloride / ethyl acetate 80/20 by volume as eluent), [2- (5,6-dimethoxy-1-methyl -1H- indol-3-yl) - 0.036 g of 1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] diethylamine is obtained, the properties of which are as follows.

- Mass Spectrum (ES): m / z = 547 (M + H) + base _{peak; m / z = 474 ((} M + H) -C 4 H 11 N) +.

(Example 200)
[2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] piperid-4-ol (A003435835 (P-33047) -129-1))
a) [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl)-] used in Example 179a according to the method described in Example 179a [2- (5,6-dimethoxy-1-methyl-1H-indole-] instead of 1H-pyrrolo [2,3-b] pyrid-4-yl-methyl] (4-trifluoromethylsulfanylbenzyl) amine Starting from 0.045 g of 3-yl) -1- (toluene-4sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] piperid-4-ol and 0.44 cm ³ of 5N potassium hydroxide , (2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] piperid-4-ol 0.031 g of [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H pyrrolo [2,3-b] pyrid-4-ylmethyl] piperid-4-ol is obtained. Its characteristics are as follows.

^-1 H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value) 1.46 (m, 2H); 1.74 (m, 2H); 2.13 (m, 2H); 2.78 ( m, 2H); 3.48 (m, 1H); 3.78 (s, 2H); 3.81 (s, 3H); 3.87 (s, 3H); 3.89 (s, 3H); 4.56 (wide m, 1H); 6.89 (wide s, 1H); 6.93 (d, J = 5.0 Hz, 1H); 7.12 (s, 1H); 7.42 (s, 1H); 7.76 (s, 1H); 8.03 (d, J = 5.0 Hz, 1H); 11.7 (wide s, 1H).

Mass spectrum (EI): m / z = 420 M ⁺ ; m / z = 321 (M−C ₅ H ₉ NO) ⁺ reference peak.

  b) [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl ] -Piperidin-4-ol can be produced by the following method.

Piperidi-4-ol 0.027 g, potassium carbonate 0.075 g and sodium iodide 0.016 g were mixed with 4-chloromethyl-2- (5,6-dimethoxy-1-methyl-1H-indole at a temperature around 20 ° C. -3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine is added to a solution of 0.055 g of acetonitrile (3 cm ³ ). The reaction medium is heated at 80 ° C. for 1 hour. After cooling, the reaction medium is filtered through a sintered funnel and the filtrate is concentrated under reduced pressure. The residue obtained is taken up in 3 cm ^{3 of} water and 4 cm ³ of ethyl acetate. After separating the phases by settling, the organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] piperidi 0.049 g of -4-ol is obtained, the properties of which are as follows:

Mass spectrum (ES): m / z = 575 (M + H) ⁺ reference peak.

  c) 4-Chloromethyl-2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b]- Pyridine can be produced by the following method.

0.089 cm ^{3 of} thionyl chloride and 5 drops of DMF were added at a temperature around 20 ° C. [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-yl] methanol is added to a solution of 0.4 g of (4 cm ³ ) methylene chloride. The reaction medium is stirred at this same temperature for 4 hours. Ice is added and the reaction medium is neutralized with saturated sodium bicarbonate solution. After separating the phases by settling, the organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. Flash - after purification by packed chromatography (SiO _2, methylene chloride / ethyl acetate 97.5 / 2.5 by volume as eluant), 4-chloromethyl-2- (5,6-dimethoxy-1-methyl -1H -Indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyridine 0.234 g is obtained, the properties of which are as follows:

- Mass Spectrum ^{(EI): m / z =} 509M +; m / z = 354M-C 7 H 7 SO 2) + base peak.

(Example 201)
1- [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] azetidin-3-ylamine (A003453957 (P -33047-148-1))
1- [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] azetidin-3-ylamine was prepared as follows: It can be manufactured by the method.

Hydrochloric acid (4N dioxane solution) 0.27 cm ³ was added at a temperature around 20 ° C. at {1- [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2, 3-b] Pyrid-4-ylmethyl] azetidin-3-yl} carbamic acid tert-butyl ester is added to a solution of 0.051 g in methanol (3 cm ³ ) and methylene chloride (0.5 cm ³ ). The reaction medium is stirred at room temperature for 24 hours. The reaction medium is concentrated under reduced pressure. The residue obtained is taken up in 4 cm ³ of water and neutralized with 1N sodium hydroxide to pH 10. Add 12 cm ³ of methylene chloride. After separating the phases by settling, the organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. 0.008 g of 1- [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] azetidin-3-ylamine The properties obtained are as follows.

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value) 2.73 (m, 2H); 3.44 (m, 1H); 3.59 (m, 2H); 3.81 ( s, 3H); 3.87 (s, 5H); 3.89 (s, 3H); 6.73 (d, J = 2.0 Hz, 1H); 6.92 (d, J = 5.0 Hz, 1H); 7.11 (s, 1H); 7.44 (s, 1H); 7.73 (s, 1H); 8.03 (d, J = 5.0 Hz, 1H); 11.65 (wide) s, 1H).

Mass spectrum (ES): m / z = 392 (M + H) ⁺ .

(Example 202)
{1- [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] azetidin-3-yl} -carbamine Acid tert-butyl ester (A003452988 (P-33047-1431))
a) [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl)-] used in Example 179a according to the method described in Example 179a {1- [2- (5,6-dimethoxy-1-methyl-1H-indole) instead of 1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] (4-trifluoromethylsulfanylbenzyl) amine -3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo- [2,3-b] pyrid-4-ylmethyl] azetidin-3-yl} carbamic acid tert-butyl ester 0.13 g and 5N Using potassium hydroxide 0.805 cm ³ as a raw material, {1- [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrrole [Lid-4-ylmethyl] azetidin-3-yl} carbamic acid tert-butyl ester is prepared. {1- [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] azetidin-3yl} carbamic acid tert -0.07 g of butyl ester is obtained, the properties of which are as follows:

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value) 1.37 (s, 9H); 2.97 (t, J = 7.0 Hz, 2H); 3.58 (t, J = 7.0 Hz, 2H); 3.81 (s, 3H); 3.88 (s, 3H); 3.90 (s, 5H); 4.10 (m, 1H); 6.73 (d, 6.91 (d, J = 5.0 Hz, 1H); 7.11 (s, 1H); 7.31 (wide d, J = 7.0 Hz, 1H); 7 .44 (s, 1H); 7.74 (s, 1H); 8.03 (d, J = 5.0 Hz, 1H); 11.7 (wide s, 1H).

Mass spectrum (ES): m / z = 492 (M + H) ⁺ reference peak; m / z = 436 (MH—C ₄ H ₈ ) ⁺ .

b) 4-Chloromethyl-2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H- according to the method described in Example 200b Starting from 0.14 g of pyrrolo [2,3-b] pyridine and 0.118 g of piperidin-4-ol instead of azetidin-3-ylcarbamic acid tert-butyl ester used in Example 200b, {1- [ 2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] -azetidine -3-yl] carbamic acid tert-butyl ester is prepared. Flash - after purification by packed chromatography (SiO _2, methylene chloride / methanol 95/5 by volume as eluant), {1- [2- (5,6-dimethoxy-1-methyl -1H- indol-3-yl ) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] azetidin-3-yl} carbamic acid tert-butyl ester 0.135 g is obtained, the properties of which are as follows.

- Mass Spectrum (ES): m / z = 646 (M + H) + base _{peak; m / z = 590 (MH} -C 4 H 8) +.

(Example 203)
{1- [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] azetidin-3-yl} -methyl Amine dihydrochloride (A003453945A (P-33047-1501))
a) According to the method described in Example 201, the {1- [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3] used in Example 201 was used. -B] pyridi-4-ylmethyl] azetidin-3-yl} carbamic acid tert-butyl ester instead of {1- [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1- (Toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] -pyrid-4-ylmethyl] azetidin-3-ylmethyl} carbamic acid tert-butyl ester 0.027 g and hydrochloric acid (4N dioxane solution) Using 1.35 cm ³ as a raw material, {1- [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-i Rumethyl] azetidin-3-yl} methylamine dihydrochloride is prepared. [Missing] 5N potassium hydroxide. {1- [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] azetidin-3-yl} methylamine -0.005 g of dihydrochloride is obtained, the properties of which are as follows:

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value) 3.83 (s, 3H); 3.88 (s, 3H); 3.92 (wide s, 3H); 2.90 ˜4.35 (very wide m partially covered, 7H total); 4.75 (m, 2H); 7.05 to 7.10 (m, 3H); 7.60 (s, 1H) 7.81 (s, 1H); 7.85 to 8.03 (wide m, 3H); 8.17 (wide d, J = 5.0 Hz, 1H); 140.7 to 11.2 (extreme) 1m (wide m, 1H).

Mass spectrum (ES): m / z = 406 (M + H) ⁺ reference peak.

(Example 204)
{1- [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] azetidin-3-yl-methyl} Carbamic acid tert-butyl ester (A003453144 (P-33047-145-1))
a) [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl)-] used in Example 179a according to the method described in Example 179a {1- [2- (5,6-dimethoxy-1-methyl-1H-indole) instead of 1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] (4-trifluoromethylsulfanylbenzyl) amine -3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] azetidin-3-ylmethyl} -carbamic acid tert-butyl ester 0.15 g and 5N Using 0.909 cm ³ of potassium hydroxide as a raw material, {1- [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3- b] Pyrid-4-ylmethyl] azetidin-3-ylmethyl} -carbamic acid tert-butyl ester is prepared. Flash - after purification by packed chromatography (SiO _2, methylene chloride / methanol 95/5 by volume as eluant), {1- [2- (5,6-dimethoxy-1-methyl -1H- indol-3-yl 0.037 g of -1- (toluene-4-sulfonyl) -1H-pyrrolo- [2,3-b] pyrid-4-ylmethyl] azetidin-3-ylmethyl} carbamic acid tert-butyl ester The characteristics are as follows.

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value) 1.36 (s, 9H); 2.97 (t, J = 7.0 Hz, 2H); 3.14 (m, 3H) 3.19-3.35 (covered m, 2H); 3.81 (s, 3H); 3.87 (s, 5H); 3.89 (s, 3H); 6.75 (d) , J = 2.0 Hz, 1H); 6.90 (wide m, 1H); 6.92 (d, J = 5.0 Hz, 1H); 7.11 (s, 1H); 7.44 (s, 1H); 7.74 (s, 1H); 8.02 (d, J = 5.0 Hz, 1H); 11.65 (wide s, 1H).

- Mass Spectrum ^{(EI): m / z =} 505M +; m / z = 321 (M-C 9 H 16 N 2 O 2) + base peak.

b) 4-Chloromethyl-2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H- according to the method described in Example 200b Starting from 0.14 g of pyrrolo [2,3-b] pyridine and 0.123 g of azetidin-3-ylmethylcarbamic acid tert-butyl ester instead of piperidi-4-ol used in Example 200b, {1- [ 2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] -azetidine -3-ylmethyl} carbamic acid tert-butyl ester is prepared. Flash - after purification by packed chromatography (SiO _2, methylene chloride / methanol 95/5 by volume as eluant), {1- [2- (5,6-dimethoxy-1-methyl -1H- indol-3-yl ) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] -azetidin-3-ylmethyl} carbamic acid tert-butyl ester 0.154 g is obtained, the properties of which are as follows.

- Mass Spectrum ^{_{(EI): m / z =}} 659M +; m / z = 505 (M-C 7 H 6 SO 2) +; m / z = 320 (m / z = 505-C 9 H 17 N 2 O ₂ ) ⁺ Reference peak.

(Example 205)
[2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -4- (4-methylpiperazin-1-ylmethyl) -1H-pyrrolo [2,3-b] pyridine (A003438870 ( P-33047-131-2))
a) [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl)-] used in Example 179a according to the method described in Example 179a [2- (5,6-dimethoxy-1-methyl-1H-indole-3) instead of 1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] (4-trifluoromethylsulfanyl-benzyl) amine -Yl) -1- (toluene-4-sulfonyl) -4- (4-methylpiperazin-1-ylmethyl) -1H-pyrrolo [2,3-b] pyridine 0.040 g and 5N potassium hydroxide 0.28 cm ³ [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -4- (4-methylpiperazin-1-ylmethyl) -1H-pyrrolo [2,3- b] Produce pyridine. [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -4- (4-methylpiperazin-1-ylmethyl) -1H-pyrrolo [2,3-b] pyridine 0.014 g Is obtained, and its characteristics are as follows.

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value) 2.15 (s, 3H); 2.30 to 2.54 (partially covered m, 8H); 3.79 (S, 2H); 3.81 (s, 3H); 3.87 (s, 3H); 3.89 (s, 3H); 6.89 (d, J = 2.0 Hz, 1H); 93 (d, J = 5.0 Hz, 1H); 7.11 (s, 1H); 7.42 (s, 1H); 7.75 (s, 1H); 8.03 (d, J = 5. 0 Hz, 1H); 11.7 (wide s, 1H).

Mass spectrum (EI): m / z = 419 M ⁺ ; m / z = 320 (M−C ₅ H ₁₁ N ₂ ) ⁺ reference peak.

b) 4-Chloromethyl-2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H- according to the method described in Example 200b Starting from 0.055 g of pyrrolo [2,3-b] pyridine and 0.03 cm ³ of 1-methylpiperazine instead of piperidi-4-ol used in Example 200b, [2- (5,6-dimethoxy- 1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -4- (4-methylpiperazin-1-ylmethyl) -1H-pyrrolo [2,3-b] pyridine is prepared. . [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -4- (4-methylpiperazin-1-ylmethyl) -1H-pyrrolo [ 0.043 g of 2,3-b] pyridine is obtained, the properties of which are as follows:

Mass spectrum (ES): m / z = 574 (M + H) ⁺ ; m / z = 308 (M + acetonitrile + 2H) ²⁺ / 2; m / z = 231 (MH + acetonitrile-C ₇ H ₇ SO ₂ + H) ²⁺ / 2 reference peaks.

(Example 206)
[2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-yl] phenylmethanol (A003403794 (P-32989-031- 1))
a) [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl)-] used in Example 179a according to the method described in Example 179a [2- (5,6-dimethoxy-1-methyl-1H-indole-] instead of 1H-pyrrolo [2,3-b] pyrid-4-yl-methyl] (4-trifluoromethylsulfanylbenzyl) amine 3-yl) -1- (toluene-4sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-yl] phenylmethanol 0.105 g and 5N potassium hydroxide 0.85 cm ³ were used as raw materials. -(5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-yl] phenylmethanol is prepared. 0.070 g of [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-yl] phenylmethanol was obtained, The characteristics are as follows.

^-1 H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value) 3.80 (s, 3 H); 3.86 (s, 3 H); 3.89 (s, 3 H); 6.11 ( 6.69 (wide s, 1H); 7.10 (s, 1H); 7.15-7.24 (m, 2H); 7.26-7.33 (m, 3H); 7.53 (wide d, J = 7.5 Hz, 2H); 7.70 (s, 1H); 8.09 (d, J = 5.0 Hz, 1H); 11.65 (wide m, 1H).

Mass spectrum (EI) (IC): m / z = 413M ⁺ reference peak.

  b) [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-yl Phenyl-methanol can be produced by the following method.

Phenylmagnesium bromide (1M in THF) 0.45 cm ³ was added at a temperature around 6 ° C. [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4- Sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] -4-carboxaldehyde is added to a solution of 0.1 g in THF (5 cm ³ ). The reaction medium is stirred at this same temperature for 30 minutes and then at room temperature for 24 hours. Add 5 cm ^{3 of} saturated ammonium chloride solution and 10 cm ³ of methylene chloride. After separating the phases by settling, the organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-yl] phenyl 0.105 g of methanol is obtained, the characteristics of which are as follows:

- Mass Spectrum ^{(EI): m / z =} 567M +; m / z = 412 (M-C 7 H 7 SO 2) + base peak.

(Example 207)
[2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-yl] propan-1-ol (A003408773 (P-32989) -039-1))
a) [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl)-] used in Example 179a according to the method described in Example 179a [2- (5,6-dimethoxy-1-methyl-1H-indole-3-] instead of 1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] (4-trifluoromethylsulfanylbenzyl) amine Yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-yl] propan-1-ol and 0.80 cm ³ of 5N potassium hydroxide as raw materials, [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-yl] propan-1-ol is prepared. 0.060 g of [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] -pyrid-4-yl] propan-1-ol is obtained. Its characteristics are as follows.

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value) 0.90 (t, J = 7.0 Hz, 3H); 1.80 (m, 2H); 3.81 (s, 3H 3.87 (s, 3H); 3.88 (s, 3H); 4.96 (m, 1H); 5.25 (d, J = 5.0 Hz, 1H); 6.75 (d, J = 2.0 Hz, 1H); 7.01 (d, J = 5.0 Hz, 1H); 7.11 (s, 1H); 7.44 (s, 1H); 7.74 (s, 1H) 8.07 (d, J = 5.0 Hz, 1H); 11.65 (wide s, 1H).

Mass spectrum (ES): m / z = 366 (M + H) ⁺ reference peak.

  b) [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-yl Propan-1-ol can be produced by the following method.

Ethylmagnesium bromide (1M in THF) 0.45 cm ³ was added at a temperature around 6 ° C. [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4- Sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] -4-carboxaldehyde is added to a solution of 0.1 g in THF (5 cm ³ ). The reaction medium is stirred at this same temperature for 30 minutes and then at room temperature for 24 hours. Add 5 cm ^{3 of} saturated ammonium chloride solution and 10 cm ³ of methylene chloride. After separating the phases by settling, the organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. Flash - after purification by packed chromatography (SiO _2, methylene chloride / ethyl acetate 80/20 by volume as eluant), 0.154 g is obtained [sic], [2- (5,6- dimethoxy-1-methyl Of 1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-yl] propan-1-ol, The characteristics are as follows.

Mass spectrum (EI): m / z = 519 M ⁺ ; m / z = 364 (M−C ₇ H ₇ SO ₂ ) ⁺ reference peak.

(Example 208)
[2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-yl] methylamine (A003435888 (P-32989-101- 2))
a) [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl)-] used in Example 179a according to the method described in Example 179a [2- (5,6-dimethoxy-1-methyl-1H-indole-3-] instead of 1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] (4-trifluoromethylsulfanylbenzyl) amine Yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-yl] methylamine 0.080 g and 5N potassium hydroxide 0.80 cm ³ were used as raw materials. (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-yl] methylamine is prepared. Flash - pack after purification by chromatography (SiO _2, methylene chloride / methanol 95/05 by volume as eluent), [2- (5,6-dimethoxy-1-methyl -1H- indol-3-yl) -1H 0.015 g of pyrrolo [2,3-b] pyrid-4-yl] -methylamine are obtained, the properties of which are as follows:

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value): 3.80 (s, 3H); 3.86 (s, 3H); 3.88 (s, 3H); 4.04 (S, 2H); 6.79 (d, J = 2.0 Hz, 1H); 7.07 (d, J = 5.0 Hz, 1H); 7.11 (s, 1H); 7.48 (s) 1H); 7.75 (s, 1H); 8.06 (d, J = 5.0 Hz, 1H); 11.65 (wide s, 1H).

Mass spectrum (EI): m / z = 336M ⁺ reference peak.

  b) [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-yl Methylamine can be produced by the following method.

0.040 g of zinc and 2 cm ³ of concentrated formic acid were mixed with [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl)- 1H-pyrrolo [2,3-b] pyrid-4-carbaldehyde oxime is added to a solution of 0.1 g of ethanol (6 cm ³ ) and water (5 cm ³ ). The reaction medium is stirred at this same temperature for 24 hours at room temperature. The reaction medium is filtered through celite and the filtrate is concentrated under reduced pressure. Add 5 cm ^{3 of} water and 10 cm ³ of methylene chloride. The reaction medium is basified to pH 10 with 1N sodium hydroxide. After separating the phases by settling, the organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-yl] methyl 0.06 g of amine is obtained, the properties of which are as follows:

- Mass Spectrum ^{(EI): m / z =} 490M +; m / z = 335 (M-C 7 H 7 SO 2) + base peak.

  c) [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-carbo Aldehyde oxime can be manufactured by the following method.

Hydroxylamine hydrochloride (0.207 g) at a temperature of around 20 ° C. [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H— Add pyrrolo [2,3-b] pyridi-4-carboxaldehyde to a solution of 0.5 g of pyridine (25 cm ³ ). The reaction medium is heated at 50 ° C. for 24 hours. The reaction medium is concentrated under reduced pressure. The resulting residue was taken up in water 10 cm ³ and methylene chloride 10 cm ^3. After separating the phases by settling, the organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. 2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-carbaldehyde oxime 0 .510 g is obtained, the characteristics of which are as follows:

Mass spectrum (EI): m / z = 350 M ⁺ reference peak; m / z = 332 (M−H ₂ O) ⁺ ; m / z = 306 (M—CH ₂ NO) ⁺ .

(Example 209)
[2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-carbaldehyde oxime (A003425653 (P-32989-091-2) ))
[2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H— used in Example 179a according to the method described in Example 179a 2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl instead of pyrrolo [2,3-b] pyrid-4-yl-methyl] (4-trifluoromethylsulfanylbenzyl) amine ) -1- (Toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-carbaldehyde oxime 0.060 g and 5N potassium hydroxide 0.60 cm ³ were used as raw materials [2- (5 , 6-Dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-carbaldehyde oxime is prepared. Flash - pack after purification by chromatography (SiO _2, methylene chloride / methanol 98/02 by volume as eluent), [2- (5,6-dimethoxy-1-methyl -1H- indol-3-yl) -1H -0.010 g of pyrrolo [2,3-b] pyrid-4-carbaldehyde oxime is obtained, the properties of which are as follows:

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value) 3.82 (s, 3H); 3.87 (s, 3H); 3.89 (s, 3H); 7.07 ( d, J = 2.0 Hz, 1H); 7.12 (s, 1H); 7.09 (d, J = 5.0 Hz, 1H); 7.45 (s, 1H); 7.80 (s, 1H); 8.11 (d, J = 5.0 Hz, 1H); 8.54 (s, 1H); 11.58 (s, 1H); 11.9 (wide s, 1H).

Mass spectrum (EI): m / z = 350 M ⁺ reference peak; m / z = 332 (M−H ₂ O) ⁺ ; m / z = 306 (M—CH ₂ NO) ⁺ .

(Example 210)
N- [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] -4-trifluoromethoxy-benzenesulfone Amide (A003453139 (P-32989-120-2))
N- [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] -4-trifluoromethoxybenzene-sulfone Amides can be prepared by the following method.

0.053 g of para-toluenesulfonic acid is mixed with N- (2,4-dimethoxybenzyl) -N- [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) at a temperature around 20 ° C. ) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] -4-trifluoromethoxybenzenesulfonamide 0.050 g is added to a solution of methylene chloride (2 cm ³ ) and toluene (5 cm ³ ). The reaction medium is stirred at this same temperature for 24 hours at room temperature and heated at a temperature close to 60 ° C. for 24 hours. After cooling, the reaction medium is concentrated under reduced pressure. Add 5 cm ^{3 of} water and 10 cm ³ of methylene chloride. The reaction medium is basified to pH 9 with 1N sodium hydroxide. After separating the phases by settling, the organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue is purified by preparative LC / MS (water / acetonitrile / TFA). The resulting solid was taken up in methylene chloride 5 cm ³ and water 2 cm ^3, and pH9 basic with 1N sodium hydroxide. N- [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] -4-trifluoromethoxybenzenesulfonamide 0.008 g is obtained, the characteristics of which are as follows:

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value): 3.82 (s, 3H); 3.88 (s, 3H); 3.90 (s, 3H); 4.38 (Wide s, 2H); 6.87 (d, J = 5.0 Hz, 1H); 6.95 (d, J = 2.0 Hz, 1H); 7.13 (s, 1H); 7.50 ( 7.55 (wide d, J = 8.5 Hz, 2H); 7.78 (s, 1H); 7.96 (wide d, J = 8.5 Hz, 2H); 8.00 ( d, J = 5.0 Hz, 1H); 8.50 (m, 1H); 11.75 (wide s, 1H).

- Mass Spectrum (EI): m / z = 560M + base _{peak; m / z = 335 (M} -C 7 H 4 SO 3 F 3) +.

(Example 211)
N- (2,4-dimethoxybenzyl) -N- [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4- Yl-methyl] -4-trifluoromethoxybenzenesulfonamide (A003423534 (P-32989-083-2))
a) [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl)-] used in Example 179a according to the method described in Example 179a 1-H-pyrrolo [2,3-b] pyrid-4-ylmethyl] (4-trifluoromethylsulfanylbenzyl) amine instead of N- (2,4-dimethoxybenzyl) -N- [2- (5,6 -Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] -4-trifluoromethoxybenzenesulfone Starting from 0.070 g of amide and 0.40 cm ³ of 5N potassium hydroxide, N- (2,4-dimethoxybenzyl) -N- [2- (5,6-dimethoxy-1-methyl-1) H-Indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] -4-trifluoromethoxybenzenesulfonamide is prepared. N- (2,4-dimethoxybenzyl) -N- [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4- 0.030 g of [Ilmethyl] -4-trifluoromethoxybenzenesulfonamide is obtained, the properties of which are as follows:

¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value) 3.46 (s, 3H); 3.63 (s, 3H); 3.83 (s, 3H); 3.87 ( 4.28 (wide s, 2H); 4.79 (wide s, 2H); 6.20-6.26 (m, 2H); 6.78 (d, J = 5.0 Hz, s, 6H); 6.88 (d, J = 8.5 Hz, 1H); 6.99 (wide s, 1H); 7.12 (s, 1H); 7.48 (s, 1H); 7.50 (1H); Wide d, J = 8.5 Hz, 2H; 7.78 (s, 1H); 7.88 (wide d, J = 8.5 Hz, 2H); 7.98 (d, J = 5.0 Hz, 1H) ); 11.75 (wide s, 1H).

Mass spectrum (ES): m / z = 711 (M + H) ⁺ reference peak.

  b) N- (2,4-dimethoxybenzyl) -N- [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H- Pyrrolo- [2,3-b] pyrid-4-ylmethyl] -4-trifluoromethoxybenzenesulfonamide can be produced by the following method.

Triethylamine 0.052Cm ³ and 4- (trifluoromethoxy) benzenesulfonyl chloride ride 0.265 cm ^3, at a temperature around 20 ° C. under an argon atmosphere (2,4-dimethoxybenzyl) [2- (5,6-dimethoxy - 1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] amine 0.200 g of methylene chloride (6 cm ³ ) Add to solution. The reaction medium is stirred at this same temperature for 24 hours. Add 2 cm ³ of water. After separating the phases by settling, the organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. Flash - Pack chromatography (SiO _2, methylene chloride / methanol 98/02 by volume as eluant) after purification by, N-(2,4-dimethoxybenzyl) -N- [2- (5,6- dimethoxy -1 -Methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] -4-trifluoromethoxybenzenesulfonamide 0.210 g Is obtained, and its characteristics are as follows.

Mass spectrum (ES): m / z = 865 (M + H) ⁺ reference peak.

(Example 212)
Thiophene-2-sulfonic acid [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-yl-methyl] amide (A003453971) (P-32989-122-3))
a) N- (2,4-dimethoxybenzyl) -N- [2- (5,6-dimethoxy-1-methyl-1H-indole-3-) used in Example 210 according to the method described in Example 210 Yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] -4-trifluoromethoxybenzenesulfonamide instead of thiophene-2-sulfonic acid (2,4-dimethoxybenzyl) [2- ( Starting from 0.1 g of 5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] amide and 0.110 g of para-toluenesulfonic acid As thiophene-2-sulfonic acid [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl - producing amides. 0.025 g of thiophene-2-sulfonic acid [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] amide The properties obtained are as follows.

^-1 H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value): 3.81 (s, 3H); 3.87 (s, 3H); 3.89 (s, 3H); 4.40 (Wide s, 2H); 6.89 (d, J = 5.0 Hz, 1H); 6.91 (d, J = 2.0 Hz, 1H); 7.11 (s, 1H); 7.19 ( dd, J = 3.5 and 5.0 Hz, 1H); 7.48 (s, 1H); 7.66 (dd, J = 1.0 and 3.5 Hz, 1H); 7.77 (s, 1H) ); 7.92 (dd, J = 1.0 and 5.0 Hz, 1H); 8.02 (d, J = 5.0 Hz, 1H); 8.51 (wide m, 1H); 11.75 ( Wide s, 1H).

Mass spectrum (EI): m / z = 482 M ⁺ ; m / z = 320 (M−C ₄ H ₄ NO ₂ S ₂ ) ⁺ reference peak.

b) [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl)-] used in Example 179a according to the method described in Example 179a 1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] (4-trifluoromethylsulfanylbenzyl) amine instead of thiophene-2-sulfonic acid (2,4-dimethoxybenzyl) [2- (5 0.150 g of 6-dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) 1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] amide and 5N hydroxylation Using 1 cm ³ of potassium as a raw material, thiophene-2-sulfonic acid (2,4-dimethoxy-benzyl) [2- (5,6-dimethoxy-1-methyl-1H-indole- 3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] amide is prepared. Thiophene-2-sulfonic acid (2,4-dimethoxybenzyl) [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyridi-4 0.100 g of -ylmethyl] -amide is obtained, the properties of which are as follows:

Mass spectrum (ES): m / z = 633 (M + H) ⁺ reference peak.

  c) (2,4-Dimethoxybenzyl) [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) according to the method described in Example 211b ) -1H-pyrrolo- [2,3-b] pyrid-4-ylmethyl] amine 0.80 g and 2-thiophenesulfonyl chloride in place of 4- (trifluoro-methoxy) benzenesulfonyl chloride used in Example 211b Using 0.114 g as a raw material, thiophene-2-sulfonic acid (2,4-dimethoxy-benzyl) [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene- 4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] amide is prepared. Thiophene-2-sulfonic acid (2,4-dimethoxy-benzyl) [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1 (toluene-4-sulfonyl) -1H-pyrrolo 0.150 g of [2,3-b] pyrid-4-ylmethyl] -amide is obtained, the properties of which are as follows:

- Mass Spectrum ^{(EI): m / z =} 786M +; m / z = 631 (M-C 7 H 7 SO 2) + base peak; m / z = 320 (m / z = 631-C 13 H 13 NO ₄ S ₂₎ ^+.

(Example 213)
N- [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] benzenesulfonamide trifluoroacetate ( A003454170A (P-32989-126-3))
a) N- (2,4-dimethoxybenzyl) -N- [2- (5,6-dimethoxy-1-methyl-1H-indole-3-) used in Example 210 according to the method described in Example 210 Yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] -4-trifluoro-methoxybenzenesulfonamide instead of N- (2,4-dimethoxybenzyl) -N- [2- ( 5,4-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] benzenesulfonamide 0.04 g and para-toluenesulfonic acid 0.045 g N- [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] benzenesulfone Producing bromide trifluoroacetate. N- [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] benzenesulfonamide trifluoroacetate 0 0.011 g is obtained, the properties of which are as follows:

^-1 H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value) 3.81 (s, 3H); 3.87 (s, 3H); 3.89 (s, 3H); 4.33 ( d, J = 6.5 Hz, 2H); 6.91 (d, J = 5.0 Hz, 1H); 6.93 (d, J = 2.0 Hz, 1H); 7.11 (s, 1H); 7.49 (s, 1H); 7.52 to 7.68 (m, 3H); 7.78 (s, 1H); 7.87 (wide d, J = 7.5 Hz, 2H); 8.01 (D, J = 5.0 Hz, 1H); 8.31 (wide t, J = 6.5 Hz, 1H); 11.8 (wide s, 1H).

Mass spectrum (ES): m / z = 477; (M + H) ⁺ .

b) [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl)-] used in Example 179a according to the method described in Example 179a 1H-pyrrolo [2,3-b] -pyrid-4-ylmethyl] (4-trifluoromethylsulfanylbenzyl) amine instead of N- (2,4-dimethoxybenzyl) -N- [2- (5 0.090 g of 6-dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] benzenesulfonamide and N- (2,4-dimethoxybenzyl) -N- [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) starting from 5N potassium hydroxide 0.6 cm ³ -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] -benzenesulfonamide is prepared. N- (2,4-dimethoxybenzyl) -N- [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4- 0.100 g of [Ilmethyl] benzenesulfonamide are obtained, the properties of which are as follows:

Mass spectrum (ES): m / z = 627 (M + H) ⁺ reference peak.

  c) (2,4-Dimethoxybenzyl) [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) according to the method described in Example 211b ) -1H-pyrrolo [2,3-b] pyrid-4-yl-methyl] amine 0.80 g and 4- (trifluoromethoxy) benzenesulfonyl chloride used in Example 211b. 110 g as a raw material, N- (2,4-dimethoxybenzyl) -N- [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) 1H-pyrrolo- [2,3-b] pyrid-4-ylmethyl] benzenesulfonamide is prepared. N- (2,4-dimethoxybenzyl) -N- [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [ 0.060 g of 2,3-b] pyrid-4-yl-methyl] benzenesulfonamide is obtained, the properties of which are as follows:

Mass spectrum (ES): m / z = 781 (M + H) ⁺ reference peak.

(Example 214)
1- [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] -3- (4-trifluoromethoxy Phenyl) urea trifluoroacetate (A003454230A (P-32989-128-2))
a) N- (2,4-dimethoxybenzyl) -N- [2- (5,6-dimethoxy-1-methyl-1H-indole-3-) used in Example 210 according to the method described in Example 210 Yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] -4-trifluoromethoxybenzenesulfonamide instead of 1- (2,4-dimethoxybenzyl) -1- [2- (5 , 6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] -3- (4-trifluoromethoxyphenyl) urea 0.04 g and Starting from 0.045 g of para-toluenesulfonic acid, 1- [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4 -Ilme ] -3- (4-trifluoromethoxyphenyl) producing urea trifluoroacetate. 1- [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] -3- (4-trifluoromethoxy 0.0015 g of phenyl) urea trifluoroacetate is obtained, the properties of which are as follows:

^-1 H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value): 3.78 (s, 3H); 3.80 (s, 3H); 3.86 (s, 3H); 4.63 (Wide d, J = 6.5 Hz, 2H); 6.78 (Wide t, J = 6.5 Hz, 1H); 6.83 (Wide s, 1H); 6.93 (d, J = 5.0 Hz) 7.10 (s, 1H); 7.22 (wide d, J = 8.5 Hz, 2H); 7.43 (s, 1H); 7.52 (wide d, J = 8.5 Hz) 2.H); 7.77 (s, 1H); 8.06 (d, J = 5.0 Hz, 1H); 8.82 (s, 1H); 11.75 (wide s, 1H).

Mass spectrum (ES): m / z = 540 (M + H) ⁺ reference peak.

b) [2- (5,6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl)-] used in Example 179a according to the method described in Example 179a 1H-Pyrrolo [2,3-b] pyrid-4-ylmethyl] (4-trifluoro-methylsulfanylbenzyl) amine instead of 1- (2,4-dimethoxybenzyl) -1- [2- (5 6-Dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-yl-methyl] -3- (4 1- (2,4-dimethoxybenzyl) -1- [2- (5,6-dimethoxy-1-methyl-1H-) using 0.150 g of (trifluoromethoxyphenyl) urea and 1 cm ³ of 5N potassium hydroxide as raw materials Indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] -3- (4-trifluoromethoxyphenyl) urea is prepared. 1- (2,4-Dimethoxy-benzyl) -1- [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyrid-4 0.040 g of -ylmethyl] -3- (4-trifluoromethoxyphenyl) urea is obtained, the properties of which are as follows:

Mass spectrum (ES): m / z = 690 (M + H) ⁺ reference peak.

  c) 1- (2,4-Dimethoxybenzyl) -1- [2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H- Pyrrolo- [2,3-b] pyrid-4-ylmethyl] -3- (4-trifluoromethoxyphenyl) urea can be produced by the following method.

4- (Trifluoromethoxy) phenylisocyanate 0.094 cm ³ is added to (2,4-dimethoxy-benzyl) [2- (5,6-dimethoxy-1-methyl-1H--) at a temperature around 20 ° C. under an argon atmosphere. Indol-3-yl) -1 (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] -amine is added to a solution of 0.080 g of methylene chloride (6 cm ³ ). The reaction medium is stirred at this same temperature for 24 hours. Add 2 cm ³ of water. After separating the phases by settling, the organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. Flash - after purification by packed chromatography (SiO _2, methylene chloride / methanol 98/02 by volume as eluant), 1- (2,4-dimethoxybenzyl) -1- [2- (5,6-dimethoxy -1 -Methyl-1H-indol-3-yl) -1- (toluene-4-sulfonyl) -1H-pyrrolo [2,3-b] pyrid-4-ylmethyl] -3- (4-trifluoromethoxyphenyl) urea 0.150 g is obtained, the properties of which are as follows:

- Mass Spectrum _{^{(EI): m / z =}} 843 (M) +; m / z = 640 (M-C 8 H 4 NO 2 F 3) +; m / z = 485 (m / z = 640-C 7 H ₇ SO ₂ ) ⁺ ; m / z = 203 (C ₈ H ₄ NO ₂ F ₃ ⁺ ) reference peak.

(Example 215)
2- [5,6-dimethoxy-1-methyl-1H-indol-3-yl] -4-methyl-1H-pyrrolo [2,3-b] pyridine (A003338710 (P-31376-043-1))
a) 2- [5,6-Dimethoxy-1-methyl-1H-indol-3-yl] -4-methyl-1H-pyrrolo [2,3-b] pyridine is prepared by the following method.

A 5N aqueous potassium hydroxide solution (1.3 cm ³⁾ was heated at a temperature of about 20 ° C. to 2- [5,6-dimethoxy-1-methyl-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -4. - methanol methyl -1H- pyrrolo [2,3-b] pyridine 0.13 g (15cm ³⁾ added to the solution. The reaction medium is refluxed for about 18 hours. The reaction mixture is evaporated under reduced pressure and the residue thus obtained is dissolved in 100 cm ³ of ethyl acetate, transferred to a separatory funnel and washed with 50 cm ³ of distilled water. The aqueous phase was re-extracted with ethyl acetate 50 cm ^3, the combined organic phases are washed successively with saturated aqueous sodium chloride solution 50 cm ³ of distilled water 50 cm ^3. The organic extract is dried over magnesium sulfate, filtered and evaporated under reduced pressure to give the crude compound, which is purified by chromatography on a Flash Chromabond RS6 SiOH cartridge (silica 3 g). . Elution was carried out with a heptane / isopropanol mixture (70/30 volume ratio) at a flow rate of 10 cm ³ / min. Fractions containing the expected compound were combined and evaporated to give 2- [5,6-dimethoxy-1-methyl-1H-indol-3-yl] -4-methyl-1H-pyrrolo [2,3-b Pyridine was obtained in the form of a pasty yellow solid (0.008 g, 8%), the properties of which are as follows:

^-1 H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ ppm value) 2.55 (s, 3 H); 3.81 (s, 3 H); 3.86 (s, 3 H); 3.89 ( 6.73 (d, J = 2.0 Hz, 1H); 6.82 (d, J = 5.0 Hz, 1H); 7.10 (s, 1H); 7.47 (s, 3H); 1H); 7.75 (s, 1H); 7.98 (d, J = 5.0 Hz, 1H); 11.65 (wide s, 1H).

Mass spectrum (ES): m / z = 322 (M + H) ⁺ .

  b) 2- [5,6-dimethoxy-1-methyl-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -4-methyl-1H-pyrrolo [2,3-b] pyridine. It is manufactured by the following method.

0.017 g of sodium hydride (60%) was added to 2- [5,6-dimethoxy-1H-indol-3-yl] -1- (toluene-4-) at a temperature around 20 ° C. under an inert atmosphere of argon. Sulfonyl) -4-methyl-1H-pyrrolo [2,3-b] pyridine is added to a solution of 0.17 g of dehydrated dimethylformamide (7 cm ³ ). After stirring for 1 hour at the same temperature, 0.025 cm ³ of methyl iodide is added. Stirring is continued at this temperature for 4 hours. The reaction mixture is taken up in 50 cm ³ of water and extracted with 100 cm ³ of ethyl acetate, and the aqueous phase is re-extracted twice with 50 cm ³ of ethyl acetate. The combined organic phases are washed successively with saturated aqueous sodium chloride solution 50 cm ³ of distilled water 50 cm ^3. After separating the phases by settling, the organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue is purified on a flash chromabond RS6 SiOH cartridge (silica 3 g). Elution was performed with a methylene chloride / methanol mixture (95/05 volume ratio) at a flow rate of 10 cm ³ / min. Fractions containing the expected compound were combined and evaporated to give 2- [5,6-dimethoxy-1-methyl-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -4-methyl. -1H-pyrrolo [2,3-b] pyridine is obtained in the form of a beige solid (0.130 g, 72%), the properties of which are as follows:

Mass spectrum (ES): m / z = 476 (M + H) ⁺ .

  c) 2- [5,6-Dimethoxy-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -4-methyl-1H-pyrrolo [2,3-b] pyridine is prepared by the following method. Manufactured by.

0.475 g of 1-tert-butyloxycarbonyl-5,6-dimethoxy-indole-3-boronic acid and 4.5 cm ³ of saturated aqueous sodium bicarbonate solution were added in this order to 1- (toluene-4-sulfonyl) -1H— 2-Iodo-4-methylpyrrolo [2,3-b] pyridine is added to a solution of 0.61 g of dehydrated dimethylformamide (14 cm ³ ). The reaction mixture is purged with argon using a spray tube for 30 minutes and 0.085 g of tetrakis (triphenylphosphine) palladium is added. The reaction medium is heated at 120 ° C. for 4 hours. After cooling, the reaction medium is filtered through celite and the filtrate is concentrated under reduced pressure. The resulting oil was taken up in water 100 cm ^3, ethyl acetate 100 cm ³ and extracted twice, twice organic phase with distilled water 50 cm ^3, is washed successively with saturated aqueous sodium chloride solution 50 cm ³ of distilled water 50 cm ³ . The organic phase is dried over magnesium sulfate in the presence of animal charcoal, filtered through celite and concentrated under reduced pressure. The resulting residue is purified on a flash chromabond RS70 SiOH cartridge (silica 35 g). Elution was carried out with a heptane / isopropanol mixture (90/10 volume ratio) at a flow rate of 10 cm ³ / min. Fractions containing the expected compound are combined and evaporated under reduced pressure. 2- [5,6-dimethoxy-1H-indol-3-yl] -1- (toluene-4-sulfonyl) -4-methyl-1H-pyrrolo [2,3-b] pyridine is thus a beige powder (0.17 g, 25%), the properties of which are as follows:

Mass spectrum (ES): m / z = 462 (M + H) ⁺ .

  1-tert-Butyloxy-carbonyl-5,6-dimethoxyindole-3-boronic acid is produced according to the method described in patent WO03 / 000688A1.

  d) 1- (Toluene-4-sulfonyl) -1H-2-iodo-4-methylpyrrolo [2,3-b] pyridine is prepared by the following method.

1.1 cm ³ of n-BuLi (2.5 M hexane solution) was added to 1- (toluene-4-sulfonyl) -1H-4-methylpyrrolo [2,3- b] Add dropwise to a solution of 0.5 g of pyridine in dehydrated tetrahydrofuran (8 cm ³ ). The reaction medium is stirred at this same temperature for 1 hour and then a solution of 0.8 g of iodine in tetrahydrofuran (4 cm ³ ) is added dropwise. The reaction medium is stirred at −78 ° C. for 15 minutes. The reaction medium is stirred for 20 hours. 50 cm ³ of water are added and the reaction medium is extracted 3 times with 100 cm ³ of ethyl acetate. The organic phase distilled water 100 cm ^3, is washed successively with saturated aqueous sodium chloride solution 100 cm ³ of distilled water 100 cm ^3. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue obtained is purified on a Macherey-Nagel cartridge (silica 15 g). Elution was carried out with a (cyclohexane / ethyl acetate) mixture (75/25, volume ratio) at a flow rate of 10 cm ³ / min. Fractions containing the expected compound were combined and evaporated under reduced pressure. 1- (Toluene-4-sulfonyl) -1H-2-iodo-4-methylpyrrolo [2,3-b] pyridine was thus obtained in the form of a brown oil (0.61 g, 43%) The characteristics are as follows.

- Mass Spectrum ^{(EI): m / z =} 412 (M) +; m / z = 348 (M-SO 2) +; m / z = 221 (m / z = 348-I) +; m / z = 91; (C ₇ H ₇ ) ⁺ reference peak.

  e) 1- (Toluene-4-sulfonyl) -1H-4-methylpyrrolo [2,3-b] pyridine is prepared by the following method.

4.020 g of triphenylphosphine, 5.4 g of lithium chloride, 2.115 g of bis (triphenylphosphine) palladium (II) chloride and 18.19 g of tetramethyltin were added at a temperature near 20 ° C. under an inert atmosphere of argon. -(Toluene-4-sulfonyl) -1H-4-iodo-pyrrolo [2,3-b] pyridine is added to a solution of 10 g of dimethylformamide (120 cm < ³ >). The reaction medium is heated at a temperature close to 120 ° C. for 20 hours. After cooling, the reaction medium is concentrated under reduced pressure. The residue obtained is taken up in 200 cm ³ of ethyl acetate and extracted twice with 50 cm ³ of water. The organic phase is dried over magnesium sulfate in the presence of animal charcoal, filtered through celite and concentrated under reduced pressure. The residue obtained is taken up in 50 mL of methanol. The resulting solid is filtered off with a sinter funnel. 5.1 g of 1- (toluene-4-sulfonyl) -1H-4-methylpyrrolo [2,3-b] pyridine is thus obtained in the form of a yellow solid, the properties of which are as follows:

- Mass Spectrum ^{(EI): m / z =} 286 (M) +; m / z = 222 (M-SO 2) + base _{peak; m / z = 91; (} C 7 H 7) +.

  f) 1- (Toluene-4-sulfonyl) -1H-4-iodo-pyrrolo [2,3-b] pyridine is prepared by the following method.

10.6 g of para-toluenesulfonyl chloride and 0.331 g of tetrabutylammonium hydrogen sulfate were added to 12 g of 1H-4-iodo-pyrrolo [2,3-b] pyridine at a temperature of about 20 ° C. under an inert atmosphere of argon. To the (425 cm ³ ) solution is added dropwise 3.1 N sodium hydroxide solution. The reaction medium is stirred for 16 hours at a temperature close to 20 ° C. After separating the phases by settling, the organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure. 19.3 g of 1- (toluene-4-sulfonyl) -1H-4-iodo-pyrrolo [2,3-b] pyridine are thus obtained, the properties of which are as follows:

- Mass Spectrum ^{(EI): m / z =} 398; (M) +; m / z = 334 (M-SO 2) + base _{peak; m / z = 91 (C} 7 H 7) +.

  Compound 1H-4-iodo-pyrrolo [2,3-b] pyridine is prepared according to methods described in the literature (Synlett, 2001, 5, 609-612).

(Example 216)
Pharmaceutical composition Tablets corresponding to the following formulation were produced.

Example 94 product: 0.2 g
Excipients for increasing the final tablet weight: 1 g
(Excipient details: lactose, talc, starch, magnesium stearate).

(Example 217)
Pharmaceutical composition Tablets corresponding to the following formulation were produced.

Example 101 product: 0.2 g
Excipients for increasing the final tablet weight: 1 g
(Excipient details: lactose, talc, starch, magnesium stearate).

(Example 218)
Pharmaceutical composition Tablets corresponding to the following formulation were produced.

Product of Example 193: 0.2 g
Excipients for increasing the final tablet weight: 1 g
(Excipient details: lactose, talc, starch, magnesium stearate).

Describes route “A” for obtaining derivatives of formula (I): 2- (1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyridine. Describes route “B” in obtaining derivatives of formula (I): 2- (Indol-3-yl) -1H-pyrrolo [2,3-b] pyridine. In the synthesis of the product of formula (I) of the present invention, a route for introducing a substituent at the R1 position and a route for introducing a substituent at the R3 position are described. In the synthesis of the product of formula (I) of the present invention, a route for introducing a substituent at the R1 position and a route for introducing a substituent at the R3 position are described. The synthesis route for obtaining 2- (1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyridine-4-carboxaldehyde derivatives is described. 1 illustrates a synthetic route for introducing a substituent R4 into a product of formula (I).

Claims (2)

Name is as follows:
2- {5,6-dimethoxy-1- [2- (4-methylpiperazin-1-yl) ethyl] -1H-indol-3-yl} -1H-pyrrolo [2,3-b] pyridine,
2- (4- {2- [5,6-Dimethoxy-3- (1H-pyrrolo [2,3-b] pyrid-2-yl) -indol-1-yl] ethyl} piperazin-1-yl) ethanol ,
2- (1- {2- [5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] pyrid-2-yl) -indol-1-yl] ethyl} piperid-4-yl) ethanol ,
1 ′-{2- [5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] pyrid-2-yl) -indol-1-yl] ethyl}-[1,4 ′] bipiperidyl,
1- {2- [5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] pyrid-2-yl) indol-1-yl] ethyl} piperid-3-ol,
2- {5,6-dimethoxy-1- [2- (4-methylperhydro-1,4-diazepin-1-yl) ethyl] -1H-indol-3-yl} -1H-pyrrolo [2,3 -B] pyridine,
2- [5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] pyrid-2-yl) indol-1-yl] -1- (4-hydroxypiperidin-1-yl) ethanone,
2- [5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] pyrid-2-yl) indol-1-yl] -1-thiazolidin-3-ylethanone,
4-{[5,6-dimethoxy-3- (1H-pyrrolo [2,3-b] pyrid-2-yl) indol-1-yl] acetyl} -1-methylpiperazin-2-one,
4-chloro-2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyridine,
2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -1H-pyrrolo [2,3-b] pyridine-4-carbonitrile,
4-chloro-2- [5,6-dimethoxy-1- (2-morpholin-4-ylethyl) -1H-indol-3-yl] -1H-pyrrolo [2,3-b] pyridine,
2- (1- {2- [3- (4-Chloro-1H-pyrrolo [2,3-b] pyrid-2-yl) -5,6-dimethoxyindol-1-yl] ethyl} piperidi-4- Yl) ethanol,
4-chloro-2- {5,6-dimethoxy-1- [2- (4-methylpiperazin-1-yl) -ethyl] -1H-indol-3-yl} -1H-pyrrolo [2,3-b ] Pyridine,
2- {5,6-dimethoxy-1- [2- (4-methylpiperazin-1-yl) ethyl] -1H-indol-3-yl} -1H-pyrrolo [2,3-b] pyridine-4- Carbonitrile,
2- (5,6-dimethoxy-1-methyl-1H-indol-3-yl) -5-fluoro-1H-pyrrolo [2,3-b] pyridine,
2- [5,6-dimethoxy-1- (2-morpholin-4-ylethyl) -1H-indol-3-yl] -5-fluoro-1H-pyrrolo [2,3-b] pyridine,
2- {5,6-dimethoxy-1- [2- (4-methylpiperazin-1-yl) ethyl] -1H-indol-3-yl] -5-fluoro-1H-pyrrolo [2,3-b] Pyridine,
2- [5-methoxy-1-methyl-3- (1H-pyrrolo [2,3-b] pyrid-2-yl) -1H-indol-6-yloxy] -1-morpholin-4-ylethanone,
2- [5-Methoxy-1-methyl-3- (1H-pyrrolo [2,3-b] pyrid-2-yl) -1H-indol-6-yloxy] -1- (4-methyl [1,4 ] Diazepan-1-yl) ethanone,
2- [5-Methoxy-1-methyl-3- (1H-pyrrolo [2,3-b] pyrid-2-yl) -1H-indol-6-yloxy] -N- [4- (4-methylpiperazine -1-yl) phenyl] aceto-amide,
2- [5-Methoxy-1-methyl-3- (1H-pyrrolo [2,3-b] pyrid-2-yl) -1H-indol-6-yloxy] -1- (4-methylpiperazine-1- Il) Ethanon,
1- {4- [2- (2-hydroxyethoxy) ethyl] piperazin-1-yl} -2- [5-methoxy-1-methyl-3- (1H-pyrrolo [2,3-b] pyrid-2 -Yl) -1H-indol-6-yloxy] ethanone,
(3aS, 6aS) -5- {2- [5-Methoxy-1-methyl-3- (1H-pyrrolo [2,3-b] -pyrid-2-yl) -1H-indol-6-yloxy] acetyl } Hexahydropyrrolo [3,4-c] pyrrol-1-one trifluoroacetate,
2- {5-Methoxy-1-methyl-6- [3- (4-methylperhydro-1,4-diazepin-1-yl) propoxy] -1H-indol-3-yl} -1H-pyrrolo [2 , 3-b] pyridine,
4-Chloro-2- {1-methyl-5-methoxy-6- [2- (4-methylpiperazin-1-yl) ethoxy] -1H-indol-3-yl} -1H-pyrrolo [2,3- b] pyridine,
4-chloro-2- {1-methyl-5-methoxy-6- [2- (4-piperidylpiperid-1-yl) ethoxy] -1H-indol-3-yl} -1H-pyrrolo [2,3 -B] pyridine,
4-Chloro-2- {5-methoxy-1-methyl-6- [2- (2-pyrrolidineethyl-amino) ethoxy] -1H-indol-3-yl} -1H-pyrrolo [2,3-b] Pyridine,
4-chloro-2- {1-methyl-5-methoxy-6- [2- (2-piperidineethyl-amino) ethoxy] -1H-indol-3-yl} -1H-pyrrolo [2,3-b] A compound belonging to pyridine ,
Racemates, enantiomers or diastereomers isomer form or a compound of an inorganic acid or or inorganic bases or which may compound an addition salt with an organic base with an organic acid. Claims as pharmaceuticals wherein the compound may be in racemic, enantiomeric or diastereomeric isomer form, or a pharmaceutically acceptable addition salt of said compound with or with an inorganic or organic base Item 1. The compound according to Item 1 .

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